united states patent and trademark office ......pentamidine (nebupent®), a prophylaxis for...

UNITED STATES PATENT AND TRADEMARK OFFICE

____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD

____________

ARADIGM CORPORATION Petitioner

v.

INSMED INCORPORATED Patent Owner

____________

Case PGR2017-_____ U.S. Patent No. 9,402,845

____________

DECLARATION OF A. BRUCE MONTGOMERY, M.D.

PTAB PAGE 1/146 ARADIGM EXHIBIT 1020

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TABLE OF CONTENTS

I. INTRODUCTION ........................................................................................ 1

II. QUALIFICATIONS ..................................................................................... 1

III. SUMMARY OF OPINIONS ........................................................................ 5

IV. STATE OF THE ART AS OF THE EARLIEST POSSIBLE PRIORITY DATE OF THE ’845 PATENT, DECEMBER 8, 2005 .............. 8

A. General Background ........................................................................... 8

B. Aerosolized Formulations ................................................................. 20

V. STATE OF THE ART AS OF THE ACTUAL FILING DATE OF THE ’845 PATENT, JANUARY 4, 2016 ................................................... 23

VI. SUMMARY OF THE ’845 PATENT ......................................................... 23

A. The ’845 Patent Discloses Broad Lists and Limited Examples Devoid of Any Details ...................................................................... 26

VII. PROSECUTION HISTORY FOR THE ’845 PATENT .............................. 28

VIII. LEVEL OF ORDINARY SKILL IN THE ART ......................................... 40

IX. CLAIM CONSTRUCTION ........................................................................ 43

A. Claim Terms Requiring Construction................................................ 44

1. “pharmaceutical formulation comprising a mixture of free quinolone antibiotic agent, a quinolone antibiotic agent encapsulated in a plurality of liposomes” ....................... 44

X. EFFECTIVE FILING DATES OF THE CLAIMS OF THE ’845 PATENT ..................................................................................................... 47

A. The ’845 Patent Is a Post-AIA Patent Eligible for PGR .................... 49

1. The effective filing date of claims 1-26 is the actual filing date of the ’845 Patent, because the ’845 Parent Apps. and the ’468 Provisional do not enable the full scope of the claims ................................................................................ 49


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2. The effective filing date of claims 1-26 is the actual filing date of the ’845 Patent, because the ’845 Parent Apps. and the ’468 Provisional lack written description of the broadly-claimed subject matter ............................................... 58

XI. NON-ENABLEMENT ANALYSIS ........................................................... 60

A. Claims 1-26 Are Invalid for Nonenablement..................................... 60

XII. LACK OF WRITTEN DESCRIPTION ANALYSIS .................................. 60

A. Claims 1-26 Are Invalid for Lack of Written Description ................. 60

XIII. SUMMARY OF PRIOR ART REFERENCES ........................................... 61

A. Finlay ................................................................................................ 61

B. Saiman .............................................................................................. 64

C. Zhanel ............................................................................................... 65

D. Ciofu ................................................................................................. 66

E. Bakker .............................................................................................. 67

F. WO’341 ............................................................................................ 71

G. Gay ................................................................................................... 73

XIV. OBVIOUSNESS ANALYSIS..................................................................... 74

B. Claims 1-6, 8, 11-12, 14-16, 19, and 23 Are Invalid as Obvious over Finlay in View of Saiman or Zhanel or Ciofu ........................... 76

1. Claim 1 ................................................................................... 77

2. Claims 2-4 .............................................................................. 92

3. Claims 5-6, 8 .......................................................................... 93

4. Claims 11-12 .......................................................................... 93

5. Claims 14-15 .......................................................................... 94

6. Claim 16 ................................................................................. 96


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7. Claim 19 ................................................................................. 97

8. Claim 23 ................................................................................. 97

C. Claim 18 is Invalid as Obvious over Finlay in view of Gay .............. 98

D. Claims 7, 9-10, 13, 17, 22, and 24-26 Are Invalid as Obvious over Finlay in view of Bakker and Saiman or Zhanel or Ciofu....... 101

1. Claims 7 and 9 ...................................................................... 103

2. Claims 10, 13, and 24 ........................................................... 104

3. Claim 17 ............................................................................... 105

4. Claims 22 and 26 .................................................................. 106

5. Claim 25 ............................................................................... 107

E. Claims 20 and 21 Are Invalid as Obvious over Finlay in view of Bakker and Gay .......................................................................... 108

F. Claims 1-26 Are Invalid as Anticipated by WO’341 ....................... 109

1. Claim 1 ................................................................................. 109

2. Claims 2-4 ............................................................................ 115

3. Claims 5-9 ............................................................................ 116

4. Claims 10-13 and 24 ............................................................. 117

5. Claims 14-15 ........................................................................ 119

6. Claims 16 and 17 .................................................................. 119

7. Claims 18 and 20-21 ............................................................. 120

8. Claims 19, 22, and 26 ........................................................... 121

9. Claims 23 and 25 .................................................................. 122

XV. SECONDARY CONSIDERATIONS ....................................................... 122


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I, A. Bruce Montgomery, M.D., declare and state as follows:

I. INTRODUCTION

1. I am a physician-scientist, and I currently hold the position of Chief

Executive Officer at Genoa Pharmaceuticals, a firm focused on treatment of

idiopathic pulmonary fibrosis.

2. I have been retained on behalf of Petitioner Aradigm Corporation

(“Petitioner” or “Aradigm”) as an independent expert consultant in the above-

referenced post grant review (“PGR”) proceeding, to provide information and

opinions on the teachings of the prior art and the state of the art with respect to the

issued claims of U.S. Patent No. 9,402,845 (“the ’845 Patent”). Ex. 1001. It is my

understanding that the ’845 Patent identifies Insmed Incorporated (“Patent Owner”

or “Insmed”) as its assignee.

3. I am being compensated for my time spent in connection with this

matter at my usual rate of $500 per hour. My compensation is in no way

contingent on the outcome of this case.

II. QUALIFICATIONS

4. My full curriculum vitae is attached as Exhibit A to this Declaration,

but I have summarized below some aspects of my CV relevant to this proceeding.


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5. I have more than 35 years of academic and professional experience in

the fields of medicine and liposomal formulations, including aerosolized liposomal

formulations, to treat pulmonary infections.

6. I am a named inventor on numerous patents and patent applications

worldwide, including over 20 issued U.S. patents, of which about 20 relate to

pulmonary infections and about 18 of which relate to aerosolized formulations of

antibiotics.

7. I received an M.D. degree in 1979 from the University of Washington

in Seattle, WA. After receiving my medical degree, I did my resident training at

the University of Washington in Seattle, WA. I completed my training in 1982.

Following my resident training, I was a Pulmonary Research Fellow for one year.

Then, for two years, I was a Pulmonary and Critical Care Medicine Fellow at the

University of California, San Francisco. For about four years after that, I was an

Instructor of Medicine and then an Assistant Professor of Medicine.

8. During this time, in the mid-1980’s, I pioneered the use of aerosolized

formulations to treat or prevent pulmonary infections. I co-invented aerosolized

pentamidine (NebuPent®), a prophylaxis for pneumocystis pneumonia (PCP), then

the most common cause of death in patients with AIDS. In pre-clinical studies

prior to the final formulation, I studied the use of liposome encapsulation of


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pentamidine. NebuPent® was approved by the U.S. Food and Drug

Administration (“FDA”) on June 15, 1989. Ex. 1031 (NebuPent®)1 at 1-2.

9. In the early 1990’s to 2000, I was employed at PathoGenesis

Corporation (“PathoGenesis”), where I eventually became Executive Vice

President of Research and Development responsible for research and development.

Notably, I co-invented and led the development of an aerosolized formulation of

tobramycin (tobramycin solution for inhalation, TOBI®). TOBI® was approved

by FDA on December 22, 1997. TOBI® is indicated for the management of cystic

fibrosis (CF) patients with Pseudomonas aeruginosa, which is a common cause of

lung/pulmonary disease and infections in CF patients. Ex. 1032 (TOBI®)2 at 2. In

1998, I received the Commissioner’s Special Citation from FDA for my work on

TOBI®. I was one of the first people outside of FDA to receive this award. In

August 2000, Chiron Corporation acquired PathoGenesis for $700 million.

10. In 2001, I founded Corus Pharma Inc. (“Corus”) to identify and

rapidly develop pharmaceuticals that improve patient’s health and quality of life in

the infectious and respiratory diseases areas. In 2006, Gilead Sciences, Inc.

1 NebuPent® on Drugs@FDA

(https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.pr

ocess) (last visited April 24, 2017) (Ex. 1031).

2 Prescribing Information for TOBI® (October 2015) (Ex. 1032).


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acquired Corus. During this time, I invented and led the development of an

aerosolized formulation of aztreonam lysine (aztreonam lysine solution for

inhalation, CAYSTON®). CAYSTON® was approved by FDA on February 22,

2010. Like, TOBI®, CAYSTON® is indicated to treat CF patients with

Pseudomonas aeruginosa. Ex. 1033 (CAYSTON®)3 at 1.

11. I have also received a number of awards during my career, including:

the Career Achievement Award from ISAM (International Society for Aerosols in

Medicine) in 2011; the Distinguished Industrial Scientist from the CF (cystic

fibrosis) Foundation in 2010; and the Breath of Life Award from the CF

Foundation in 2007 and 2010.

12. I have over 35 peer-reviewed publications on inhaled antimicrobials,

including the following two articles published in the New England Journal of

Medicine (“NEJM”): (1) Leoung GS, Feigal DW Jr, Montgomery AB, et al.,

“Aerosolized pentamidine for prophylaxis against Pneumocystis carinii

pneumonia,” NEJM 1990; 323:769-75 and (2) Ramsey, BW, Pepe, MS, Quan, JM,

Otto, KL, Montgomery, AB, et al., “Intermittent Administration of Inhaled

Tobramycin in Patients with Cystic Fibrosis,” NEJM 1999; 340:23-30. In

addition, in 2010, I co-chaired a workshop for FDA on end points for trials of

aerosolized antibiotics for CF patients.

3 Prescribing Information for CAYSTON® (2014) (Ex. 1033).


5

III. SUMMARY OF OPINIONS

13. My opinions in this Declaration are based on documents I have

reviewed in connection with this proceeding, and are further informed by my

knowledge and experience, including my decades of experience developing

pharmaceutical formulations, including aerosolized liposomal formulations, to treat

pulmonary infections. A list of the documents and materials that I considered in

connection with the development of my opinions set forth in this declaration is

attached hereto as Exhibit B.

14. The claims of the ’845 Patent are generally directed to methods of

treating pulmonary infections using aerosolized formulations. In my opinion, a

person of ordinary skill in the art (“POSITA”) would have been an individual or

team with an advanced degree (such as an M.D. or Ph.D.) in the field of molecular

biology, biochemistry, microbiology, engineering, or a related field and one to two

years of post-graduate experience with a focus on aerosolized delivery of

medication.

15. In my opinion, the broadest reasonable interpretation of the term

“pharmaceutical formulation comprising a mixture of free quinolone antibiotic

agent, a quinolone antibiotic agent encapsulated in a plurality of liposomes” in

claim 1 of the ’845 Patent is “pharmaceutical formulation comprising a pre-


6

nebulized or post-nebulized mixture of free quinolone antibiotic agent, a quinolone

antibiotic agent encapsulated in a plurality of liposomes.”

16. In my opinion, none of the parent applications of the ’845 Patent (“the

’845 Parent Apps.”) or U.S. Provisional Application No. 60/748,468 (“the ’468

Provisional”) enable the full scope of claims 1-26. Those claims are not entitled to

the benefit of the filing date of any of the ’845 Parent Apps. or the ’468

Provisional; instead, the effective filing date is the actual filing date of the ’845

Patent, January 4, 2016.

17. In my opinion, the ’845 Parent Apps. and the ’468 Provisional do not

provide written description of the subject matter of claims 1-26. Those claims are

not entitled to the benefit of the filing date of any of the ’845 Parent Apps. or the

’468 Provisional; instead, the effective filing date is the actual filing date of the

’845 Patent, January 4, 2016.

18. In my opinion, claims 1-26 are invalid for lack of enablement.

19. In my opinion, claims 1-26 are invalid for lack of written description.

20. In my opinion, claims 1-6, 8, 11-12, 14-16, 19, and 23 are invalid as

obvious over Finlay et al., “Regional lung deposition of nebulized liposome-

encapsulated ciprofloxacin,” International Journal of Pharmaceutics, 167:121-127

(1998) (“Finlay”) (Ex. 1024) in view of Saiman et al., “Antibiotic Susceptibility of

Multiply Resistant Pseudomonas aeruginosa Isolated from Patients with Cystic


7

Fibrosis, Including Candidates for Transplantation,” Clinical Infectious Diseases,

23:532-537 (September 1996) (“Saiman”) (Ex. 1025) or Zhanel et al., “A Critical

Review of the Fluoroquinolones Focus on Respiratory Tract Infections,” Drugs, 62

(1), pp. 13-59 (2002) (“Zhanel”) (Ex. 1026) or Ciofu et al., “Occurrence of

Hypermutable Pseudomonas aeruginosa in Cystic Fibrosis Patients is Associated

with the Oxidative Stress Caused by Chronic Lung Inflammation,” Antimicrobial

Agents and Chemotherapy, Vol. 49, No. 6, pp. 2276-2282 (June 2005) (“Ciofu”)

(Ex. 1027).

21. In my opinion, claim 18 is invalid as obvious over Finlay (Ex. 1024)

in view of Gay et al., “In Vitro Activities of Norfloxacin and Ciprofloxacin

Against Mycobacterium tuberculosis, M. avium Complex, M. chelonei, M.

fortuitum, and M. kansaii,” Antimicrobial Agents and Chemotherapy, Vol. 26, No.

1, pp. 94-96 (July 1984) (“Gay”) (Ex. 1028).

22. In my opinion, claims 7, 9-10, 13, 17, 22, and 24-26 are invalid as

obvious over Finlay (Ex. 1024) in view of Bakker-Woudenberg et al.,

“Ciprofloxacin in Polyethylene Glycol-Coated Liposomes: Efficacy in Rat Models

of Acute or Chronic Pseudomonas aeruginosa Infection,” Antimicrobial Agents

and Chemotherapy, Vol. 46, No. 8, pp. 2575-2581 (August 2002) (“Bakker”) (Ex.

1029) and Saiman (Ex. 1025) or Zhanel (Ex. 1026) or Ciofu (Ex. 1027).


8

23. In my opinion, claims 20 and 21 are invalid as obvious over Finlay

(Ex. 1024) in view of Bakker (Ex. 1029) and Gay (Ex. 1028).

24. As noted above, in my opinion, the effective filing date of claims 1-26

is the actual filing date of the ’845 Patent, January 4, 2016; thus, claims 1-26 are

invalid as anticipated by International Patent Pub. No. WO2008/063341

(“WO’341”) (Ex. 1030).

IV. STATE OF THE ART AS OF THE EARLIEST POSSIBLE PRIORITY DATE OF THE ’845 PATENT, DECEMBER 8, 2005

A. General Background

Liposomes

25. Liposomes are vesicles that have been used for decades to transport

drugs into the body. Liposomes (depicted below) are spherical vesicles with at

least one lipid bilayer that encloses an aqueous space.


9

Typically, the lipid bilayer is made of phospholipids. Ex. 1034 (Betageri)4 at 75.

Phospholipids are a class of lipids with a hydrophilic (water-loving) head and two

hydrophobic (water-hating) fatty acid “tails.” In the figure above on the left, each

phospholipid comprises one green hydrophilic head and two yellow hydrophobic

fatty acid “tails.” The fatty acid “tails” create the hydrophobic bilayer, and in the

center of the liposome is the hydrophilic aqueous space.

26. Liposomes were first described in 1965, and by the late 1980’s/early

1990’s, liposomes were being used as drug delivery vehicles. Ex. 1034 (Betageri)

at 6. By entrapping or encapsulating drugs, liposomes can ameliorate the toxicity

of entrapped drugs while maintaining drug efficacy. Ex. 1035 (Cullis 1987)6 at 4.

Liposomes also provide sustained release of the encapsulated drug; depending on

the liposome composition and encapsulated drug, liposomes provide sustained

4 Betageri et al., Liposome Drug Delivery Systems, (Technomic Publishing Co. ed.,

1993) (excerpted) (“Betageri”) (Ex. 1034).

5 Except for citations to patents and patent publications (which refer to the

originally-published column and line numbers in the following format __:__-__),

this Declaration cites to the page numbers added at the bottom of each Exhibit (and

designated “PTAB PAGE __/__”).

6 Cullis et al., “Liposomes as Pharmaceuticals,” Liposomes From Biophysics to

Therapeutics, pp. 39-72 (M. Ostro ed., 1987) (“Cullis 1987”) (Ex. 1035).


10

drug release through pores created in the lipid bilayer, via vesicle disruption due to

interactions with other agents (such as cell membranes), or by diffusion of the drug

through the lipid bilayer.

27. Generally, liposomes are unilamellar (i.e., one lipid bilayer) or

multilamellar (i.e., multiple lipid bilayers). Ex. 1035 (Cullis 1987) at 4; Ex. 1034

(Betageri) at 7. There are two types of unilamellar vesicles: small unilamellar

vesicles (SUVs) and large unilamellar vesicles (LUVs). Ex. 1035 (Cullis 1987) at

7; Ex. 1034 (Betageri) at 7. The difference between SUVs and LUVs is size.

SUVs are typically 20-40 nm in diameter; LUVs are generally greater than 100 nm

in diameter but can range between about 50 nm to about 200 nm. Id.

Multilamellar vesicles (MLVs) have “relatively large diameter[s] (>400 nm).” Ex.

1035 (Cullis 1987) at 7.

28. LUVs can be created by extrusion procedures where the phospholipid

preparation is extruded through a pore size filter of a certain size. Ex. 1035 (Cullis

1987) at 11; Ex. 1036 (Fenske)7 at 10. The extrusion procedure is akin to making a

bubble with a bubble wand (most bubbles have a similar diameter as the bubble

7 Fenske et al., “Encapsulation of weakly-basic drugs, antisense olidonucleotides,

and plasmid DNA within large unilamellar vesicles for drug delivery applications,”

Liposomes Second Edition A Practical Approach, pp. 167-191 (V. Torchilin et al.

eds., 2003) (“Fenske”) (Ex. 1036).


11

wand). Likewise, most LUVs created by the extrusion procedure are about the size

of the pore size filter; the mean diameter of the LUVs is roughly the size of the

pore size filter. Ex. 1036 (Fenske) at 10 (“extruded, at relatively high pressures

(200-400 psi), through polycarbonate filters with a pore size ranging from 30-400

nm, giving rise to narrow, monodisperse vesicle populations with diameters close

to the chosen pore size”) (emphasis added); Ex. 1035 (Cullis 1987) at 11

(“extrusion … through … 100-nm pore size results in a relatively homogeneous

population of LUV[s] with a mean diameter of approximately 90 nm”), 14

(“extrusion … through 0.1 µm filters yields LUV systems (mean diameter = 0.11

µm)”). In this way, the extrusion procedure generates a desired LUV size. Ex.

1036 (Fenske) at 10 (“extruded, at relatively high pressures (200-400 psi), through

polycarbonate filters with a pore size ranging from 30-400 nm, giving rise to

narrow, monodisperse vesicle populations with diameters close to the chosen pore

size”) (emphasis added).

29. To use liposomes as drug delivery vehicles, it is well known in the art

that the drug needs to be efficiently loaded, which “is often not a trivial problem.”

Ex. 1035 (Cullis 1987) at 11 (emphasis added). That is “because the physical and

chemical characteristics of commonly employed drugs vary considerably.” Id.

30. Creating a liposome for a given drug is not a simple task. The

chemical properties of drugs play an important role. Chemical properties (e.g.,


12

drug solubility, pKa, molecular weight, and hydrophilicity (or in the alternative,

lipophilicity) as measured by logP) affect which drug loading/trapping methods

can be used.

31. One method of loading drugs into liposomes is called passive

loading/trapping. With this technique, the “lipid and drug are codispersed in an

aqueous buffer, thus achieving entrapment while the liposomes are being formed.”

Ex. 1037 (Cullis 1989)8 at 10. There are a number of techniques to increase the

amount of drug entrapped in liposomes with the passive loading/trapping method,

including using “organic solvents or detergents” or “freeze-thaw and dehydration-

rehydration procedures.” Id. But unless the drug is “extremely water soluble (e.g.,

100 mg/ml),” “high drug-to-lipid ratios are difficult to achieve” with the passive

loading/trapping method. Id.

32. Another method of loading drugs into liposomes is called active

loading/trapping. With this technique, “the drug is loaded after the liposomes have

been formed.” Ex. 1037 (Cullis 1989) at 13. To use this method, gradients across

the lipid bilayer are created to transport the drug across the lipid bilayer into the

8 Cullis et al., “Generating and loading of liposomal systems for drug-delivery

applications,” Advanced Drug Delivery Reviews, 3, pp. 267-282 (1989) (“Cullis

1989”) (Ex. 1037).


13

enclosed aqueous space in the center of the liposome. Ex. 1037 (Cullis 1989) at

13. Some examples of active loading/trapping are as follows:

Ex. 1036 (Fenske) at 14. To create the proper gradient, a POSITA must account

for at least the liposome composition and chemical properties of the drug (e.g.,

solubility, pKa, molecular weight, and hydrophilicity (or in the alternative,

lipophilicity) as measured by logP).

Aminoglycosides and Quinolones

33. As the Patent Owner has acknowledged in the ’845 Patent and the

prosecution history, aminoglycosides and quinolones are two “distinct class[es] of


14

antiinfectives” with distinct properties. Ex. 1003 (prosecution history of the ’845

Patent) at 196-205 (5/20/16 Response) at 201. They have very different chemical

structures (e.g., aminoglycosides comprise a sugar core whereas quinolones

comprise a bicyclic core where one of the rings contains nitrogen):

Aminoglycosides Quinolones

Tobramycin

General structure

Amikacin

Ciprofloxacin

Sisomicin

34. Amikacin (a type of aminoglycoside) and ciprofloxacin (a type of

quinolone) are also distinct antibiotics with distinct properties. For example,

amikacin is extremely water soluble (185 mg/mL), but ciprofloxacin is not (<0.1

mg/mL and up to about 30 mg/mL, with a 0.3 mg/mL solubility at pH 6). Ex. 1038


15

(Drug Bank for amikacin)9 at 7; Ex. 1039 (Drug Bank for ciprofloxacin)10 at 12;

Ex. 1040 (Yu)11 at 3, Figure 3; Ex. 1037 (Cullis 1989) at 10 (“extremely water

soluble (e.g., 100 mg/ml)”). In fact, amikacin is nearly seven orders of magnitude

more hydrophilic than ciprofloxacin. Compare Ex. 1038 (Drug Bank for

amikacin) at 7 and Ex. 1039 (Drug Bank for ciprofloxacin) at 12 (amikacin has a

logP value12 of -7.4 and ciprofloxacin has a logP value of 0.28). Because of

amikacin’s high water solubility, passive loading is an acceptable method for

loading amikacin into liposomes. In contrast, ciprofloxacin is the least soluble in

water around physiological pH, making ciprofloxacin a poor candidate for passive

loading/trapping:

9 Amikacin – DrugBank (https://www.drugbank.ca/drugs/DB00479) (last visited

April 14, 2017) (Ex. 1038).

10 Ciprofloxacin – DrugBank (https://www.drugbank.ca/drugs/DB00537) (last

visited April 14, 2017) (Ex. 1039).

11 Yu et al., “The Effect of Temperature and pH on the Solubility of Quinolone

Compounds: Estimation of Heat of Fusion,” Pharmaceutical Research, Vol. 11,

No. 4, pp. 522-527 (1994) (“Yu”) (Ex. 1040).

12 LogP (or the partition coefficient) measures the “hydrophilicity” of a substance.

The lower the logP number, the more hydrophilic the substance.


16

Ex. 1040 (Yu) at 3, Figure 3. Instead, to efficiently load ciprofloxacin into

liposomes at physiological pH, a POSITA would have to create and use an active

loading/trapping method.

Nebulizers

35. Liposomal formulations can be administered in a variety of ways, e.g.,

intravenously or in aerosolized form via nebulizers. Ex. 1024 (Finlay); Ex. 1029

(Bakker); Ex. 1034 (Betageri) at 21, 23 (“liposomal routes of administration” are,

e.g., “intravenous” and “lung administration”). A nebulizer is a drug delivery

device used to administer drugs in the form of a mist that is inhaled into the lungs.

The following is an image of a nebulizer:


17

Ex. 1041 (Asthma Center website)13.

36. In general, nebulizers use oxygen, compressed air, ultrasonic power,

or a vibrating plate or mesh to break up solutions and suspensions into small

aerosol droplets that can be directly inhaled from the mouthpiece or face mask.

See, e.g., Ex. 1042 (Cipolla 1994)14. But it is well known in the art that less than

all of the liposome-encapsulated drug initially loaded into the nebulizer gets

delivered to the lungs of the patient. There are two factors that impact how much

drug gets delivered to the patient.

37. First, it is well known that different nebulizers have different

efficiencies (i.e., the percentage of the amount of drug loaded into the nebulizer 13 Asthma Center website

(http://www.theasthmacenter.org/index.php/disease_information/asthma/using_spe

cial_devices/nebulizer_instructions/) (last visited April 14, 2017) (Ex. 1041).

14 Cipolla et al., “Assessment of aerosol delivery systems for recombinant human

deoxyribonuclease,” S.T.P. Pharma Sciences, 4(1), pp. 50-62 (1994) (“Cipolla”)

(Ex. 1042).


18

that is delivered in respirable size droplets to the lungs of the patient). Ex. 1024

(Finlay) at 5, Fig. 2 (% inhaled ranging from 14 ± 1% to 34.5 ± 0.25%); Ex. 1003

(prosecution history of the ’845 Patent) at 341-346 (Rau publication) at 345, Table

1 (% inhaled ranging from 8.7 ± 1% to 38.7 ± 1.3%); Ex. 1042 (Cipolla 1994) at 7,

Table II and Table IV (% delivery, which is the amount of respirable size droplets,

ranging from “10.3 (7.3-13.4)” to “49.3 (46.0-52.1)”); Ex. 1043 (Sangwan)15 at 6

(the AERx system has “80%” efficiency “in depositing drug in the lungs”).

38. Second, it is well known in the art that nebulizers can disrupt (e.g.,

break open, rupture, or cause leakage in) liposomes upon nebulization. Ex. 1044

(Niven)16 at Abstract (“In all experiments[, the liposome-encapsulated drug] was

released from the liposomes while being aerosolized …”), 4 (“For all liposome

compositions tested[,] there was a release of encapsulated [drug] to the

surrounding buffer solution during nebulization.”); Ex. 1024 (Finlay) at 2

(“Although nebulization is often the easiest method of delivery[,] from a

15 Sangwan et al., “Aerosolized Protein Delivery in Asthma: Gamma Camera

Analysis of Regional Deposition and Perfusion,” Journal of Aerosol Medicine,

Vol. 14, no. 2, pp. 185-195 (2001) (“Sangwan”) (Ex. 1043).

16 Niven et al., “Nebulization of Liposomes. I. Effects of Lipid Composition,”

Pharmaceutical Research, Vol. 7, No. 11, pp. 1127-1133 (1990) (“Niven”) (Ex.

1044).


19

formulation point of view, several factors make such delivery an uncertain

proposition. Two such factors include disruption of liposomes by nebulization …)

(emphasis added). Because of such disruption, even less liposome-encapsulated

drug gets delivered to the lungs of the patient.

Pulmonary Infections

39. There are a number of pulmonary infections caused by infective

agents (such as bacteria). For example, Pseudomonas aeruginosa is a well-known

bacterium that causes chronic lung/pulmonary infections. Ex. 1025 (Saiman) at 4

(around 1996, it was known that “81% of American patients with CF [were]

infected with P[seudomonas] aeruginosa by their mid-twenties.”). Mycobacteria

also cause pulmonary infections. For instance, Mycobacterium tuberculosis causes

tuberculosis, and the Mycobacterium avium complex causes Mycobacterium

avium-intracellulare infection (MAI). To determine whether an antibiotic (drug)

will effectively treat a pulmonary infection caused by a particular bacterium, a

POSITA considers the minimum inhibitory concentration (MIC), which is the

minimum concentration of drug that inhibits the growth of a target microorganism,

e.g., a bacterium. As discussed below, Patent Owner also relied on MIC values in

the patent and during prosecution of the ’845 Patent. The MIC is determined for a

given isolate (which is a particular type of the target microorganism). To

determine how well the drug works on a population of the same microorganism, a


20

POSITA would perform testing on a number of isolates. MIC50 is the minimum

concentration that inhibits the growth of 50% of isolates, and MIC90 is the

minimum concentration that inhibits the growth of 90% of isolates. Ex. 1026

(Zhanel) at 10, 12. POSITAs typically look to the MIC50 values to determine how

much drug is necessary to be effective in the ’845 Patent.

B. Aerosolized Formulations

40. For decades, aerosolized formulations of free (or unencapsulated)

antibiotics have been known in the art. In the mid-1980s, I pioneered the use of

aerosolized formulations to treat pulmonary infections. I co-invented an

aerosolized formulation of pentamidine (NebuPent®) in the mid-1980’s, a

prophylaxis for pneumocystis pneumonia (PCP), then the most common cause of

death in patients with AIDS. I also co-invented an aerosolized formulation of

tobramycin (TOBI®) in the mid-1990’s, and invented an aerosolized formulation

of aztreonam (CAYSTON®) in the mid to late 2000’s. TOBI® and CAYSTON®

are indicated to treat CF patients with Pseudomonas aeruginosa.

41. Prior to December 8, 2005, aerosolized formulations with liposome-

encapsulated antibiotics were known. See, e.g., Ex. 1045 (Pilkiewicz)17 at [0072]

17 U.S. Patent Publication No. 2004/0009126 (“Pilkiewicz”) (Ex. 1045).


21

(liposome-encapsulated formulation of amikacin); Ex. 1046 (Wichert)18 at 4

(“Amikacin-containing liposomes were aerosolized using a Collison nebulizer

…”). Also, prior to December 8, 2005, aerosolized formulations with liposome-

encapsulated quinolones (such as ciprofloxacin) were known. See, e.g., Ex. 1024

(Finlay) at Title (“nebulized liposome-encapsulated ciprofloxacin”); Ex. 1047

(Wong)19 at Abstract (“Following administration of … liposome-encapsulated

ciprofloxacin by … aerosol inhalation …”); Ex. 1048 (Conley)20 at Title (“Aerosol

Delivery of Liposome-Encapsulated Ciprofloxacin: Aerosol Characterization and

Efficacy against Francisella tularensis Infection in Mice”).

18 Wichert et al., “Amikacin liposomes: characterization, aerosolization, and in

vitro activity against Mycobacterium avium-intracellulare in alveolar

macrophages,” International Journal of Pharmaceutics, 78, pp. 227-235 (1992)

(“Wichert”) (Ex. 1046).

19 Wong et al., “Liposome delivery of ciprofloxacin against intracellular

Francisella tularensis infection,” Journal of Controlled Release, 92, pp. 265-273

(2003) (“Wong”) (Ex. 1047).

20 Conley et al., “Aerosol Delivery of Liposome-Encapsulated Ciprofloxacin:

Aerosol Characterization and Efficacy against Francisella tularensis Infection in

Mice,” Antimicrobial Agents and Chemotherapy, Vol. 41, No. 6, pp. 1288-1292

(June 1997) (“Conley”) (Ex. 1048).


22

42. Prior to December 8, 2005, formulations and treatments using a

combination of immediate and sustained drug release were known. See, e.g., Ex.

1049 (Sunamoto 1984)21 at 11 (“36% of the antibiotics [sisomycin [sic]]

administered were encapsulated in OPA-112(4.9)-coated LUV, which means that

64% of the antibiotic was free and could kill bacteria present in the exterior of

cells”); id. at 14; Ex. 1050 (Sunamoto 1989)22 at 9-10 (“36% of the antibiotics

[sisomycin [sic]] administered were encapsulated in the polysaccharide-coated

LUV. This means that 64% of antibiotics were free of liposome encapsulation and

were able to kill bacteria present at the exterior of cells”). Also, prior to December

8, 2005, formulations and treatments using a combination of immediate and

sustained drug release of ciprofloxacin were known, including aerosolized

formulations of free and liposome-encapsulated ciprofloxacin. See, e.g., Ex. 1024

(Finlay) at 2 (disclosing formulations of free and liposome-encapsulated

21 Sunamoto et al., “Unexpected Tissue Distribution of Liposomes Coated With

Amylopectin Derivatives And Successful Use In The Treatment Of Experimental

Legionnaires’ Diseases,” Receptor-Mediated Targeting of Drugs, Vol. 82, pp. 359-

371 (G. Gregoriadis et al. eds., 1984) (“Sunamoto 1984”) (Ex. 1049).

22 Sunamoto et al., “Improved drug delivery directed to specific tissue using

polysaccharide-coated liposomes,” Multiphase Biomedical Materials, pp. 167-190

(T. Tsuruta et al. eds., 1989) (“Sunamoto 1989”) (Ex. 1050).


23

ciprofloxacin), 5, Fig. 2 (same); Ex. 1029 (Bakker) at 3, table 2 (disclosing

administering free (CIP) and liposome-encapsulated (PL Cipro) ciprofloxacin).

V. STATE OF THE ART AS OF THE ACTUAL FILING DATE OF TH E ’845 PATENT, JANUARY 4, 2016

43. There are no significant advances in aerosolized liposomal

formulations that are relevant here. Most of the advances have been in areas of

improved manufacturing methods to obtain greater yields or better quality control,

improved analytical techniques for documentation purposes, and improved clinical

data.

VI. SUMMARY OF THE ’845 PATENT

44. Sole independent claim 1 of the ’845 Patent is generally directed to a

method of treating pulmonary infections using liposome formulations. Ex. 1001

(’845 Patent) at claim 1. Claim 1 recites:

1. A method for treating or providing prophylaxis against a pulmonary

infection in a patient in need thereof, comprising:

administering to the lungs of the patient via an inhalation

delivery device, a pharmaceutical formulation comprising a

mixture of free quinolone antibiotic agent, a quinolone

antibiotic agent encapsulated in a plurality of liposomes, and

a pharmaceutical excipient, wherein the formulation is a

solution or a suspension, the ratio by weight of free

quinolone antibiotic agent to the encapsulated quinolone

antibiotic agent is between about 1:10 and about 10:1 and


24

the lipid component of the plurality of liposomes consists of

electrically neutral lipids,

wherein the pharmaceutical formulation is administered as an

aerosolized pharmaceutical formulation, and the aerosolized

pharmaceutical formulation comprises free quinolone

antibiotic agent in an amount effective to provide immediate

bactericidal activity against the pulmonary infection and

liposomal encapsulated quinolone antibiotic agent in an

amount effective to provide sustained bactericidal activity

against the pulmonary infection.

Id.

45. The ’845 Patent merely applies the well-known concept of drug

formulations providing immediate and sustained treatment of a disease or infection

to aerosolized formulations of quinolones for treating pulmonary infections.

46. Dependent claims 2-4 and 24 further limit the “quinolone antibiotic

agent” to fluoroquinolones (quinolones with a fluorine atom attached to the

bicyclic core) (dependent claim 2) or specific quinolones, such as ciprofloxacin

(dependent claims 2-4 and 24).

47. Dependent claims 5-9 further limit the “electrically neutral lipids” of

the liposomes to specific formulations: “electrically neutral lipids consist of an

electrically neutral phospholipid and a sterol” (dependent claim 5), “electrically

neutral lipids consist of a phosphatidylcholine and a sterol” (dependent claim 6),


25

“electrically neutral lipids consist of [hydrogenated soy phosphatidylcholine

(HSPC)] and a sterol” (dependent claim 7), “electrically neutral lipids consist of a

phosphatidylcholine and [cholesterol]” (dependent claim 8), and “electrically

neutral lipids consist of [hydrogenated soy phosphatidylcholine (HSPC)] and

[cholesterol]” (dependent claim 9).

48. Dependent claims 10-13 further limit (a) the “electrically neutral

lipids” of the liposomes to specific formulations and (b) the free and liposome-

encapsulated drug to fluoroquinolone or ciprofloxacin: “electrically neutral lipids

consist of hydrogenated soy phosphatidylcholine (HSPC) and cholesterol” and

fluoroquinolone (dependent claim 10), “electrically neutral lipids consist of a

phosphatidylcholine and a sterol” and ciprofloxacin (dependent claim 11),

“electrically neutral lipids consist of a phosphatidylcholine and cholesterol” and

ciprofloxacin (dependent claim 12), and “electrically neutral lipids consist of

hydrogenated soy phosphatidylcholine (HSPC) and cholesterol” and ciprofloxacin

(dependent claim 13).

49. Dependent claims 14 and 15 further limit the size of the liposomes to

specific ranges of mean diameters, “0.01 micron[s] to 3.0 microns” and “0.2

micron[s] to 1.0 micron,” respectively.


26

50. Both dependent claims 16 and 17 further limit the range of weight

ratios of free and liposome-encapsulated drug to “between about 1:2 and about

2:1.”

51. Dependent claims 18, 20-21, and 26 further limit the pulmonary

infection to “a mycobacterial infection” (dependent claims 18 and 20), “an

intracellular pulmonary infection” (dependent claim 21), and “a Pseudomonas

aeruginosa infection” (dependent claims 26).

52. Both dependent claims 19 and 22 further limit the patient’s condition

to “bronchiectasis.”

53. Both dependent claims 23 and 25 further limit the “inhalation delivery

device” to a “nebulizer.”

A. The ’845 Patent Discloses Broad Lists and Limited Examples Devoid of Any Details

54. The ’845 Patent is generally directed to a “system for treating or

providing prophylaxus [sic] against a pulmonary infection” comprising a

“pharmaceutical formulation comprising a mixture of free antiinfective and

antiinfective encapsulated in a lipid-based composition” and “an inhalation

device.” Ex. 1001 (’845 Patent) at Abstract.

55. Although the claims are directed to quinolones (see claim 1), the only

disclosures of quinolones, elsewhere in the patent, are as part of broad lists of

exemplary antiinfective agents:


27

Non-limiting examples of antibiotic agents that may be

used in the antiinfective compositions of the present

invention include cephalosporins, quinolones and

fluoroquinolones, penicillins, and beta lactamase

inhibitors, carbepenems, monobactams, macrolides and

lincosamines, glycopeptides, rifampin, oxazolidonones,

tetracyclines, aminoglycosides, streptogramins,

sulfonamides, and others. Each family comprises many

members.

Ex. 1001 (’845 Patent) at 9:19-26.

56. There are only two embodiments in the specification disclosing

quinolones and those disclosures are as part of broad lists of possible antiinfective

agents.

In a further embodiment, the antiinfective is an antibiotic

selected from the group consisting of cephalosporins,

quinolones, fluoroquinolones, penicillins, beta lactamase

inhibitors, carbepenems, monobactams, macrolides,

lincosamines, glycopeptides, rifampin, oxazolidonones,

tetracyclines, aminoglycosides, streptogramins, and

sulfonamides.

Ex. 1001 (’845 Patent) at 3:10-19, 4:4-13 (same).

57. No embodiments in the specification are limited only to quinolones.

No examples in the patent relate to quinolone-containing formulations.


28

58. The only two examples in the ’845 Patent (see Ex. 1001 (’845 Patent)

at 13:32-14:36) are directed to amikacin, an aminoglycoside, which is a “distinct

class” of drug from quinolones. Ex. 1003 (prosecution history of the ’845 Patent)

at 196-205 (5/20/2016 Response). Example 1 discloses the pharmacokinetics of a

“nebulized liposomal amikacin [formulation that] contains a mixture of

encapsulated (ca., 60%) and free amikacin (ca., 40%).” Ex. 1001 (’845 Patent) at

13:36-14:3. Example 2 discloses the “impact of free amikacin on the percentage of

amikacin encapsulated in liposomes following nebulization.” Id. at 14:5-36.

59. Those two examples provide no guidance or description of the

liposomes used to encapsulate the amikacin. The ’845 Patent does not disclose

how those amikacin-encapsulated liposomes were made. And the ’845 Patent does

not describe which nebulizer was used.

VII. PROSECUTION HISTORY FOR THE ’845 PATENT

60. The patent application for the ’845 Patent was filed on January 4,

2016. Ex. 1001 (’845 Patent) at 1, (22). On April 1, 2016, the Examiner rejected

all of the claims on two grounds: double patenting and obviousness. Ex. 1003

(prosecution history of the ’845 Patent) at 107-118 (4/1/16 Non-Final Office

Action).

61. With respect to the double patenting rejection, the Examiner cited

Patent Owner’s U.S. Patent No. 8,673,349 (“the ’349 Patent”) (Ex. 1014)—which,


29

like the ’845 Patent (as discussed infra), is a continuation of a series of

continuation applications stemming from U.S. Patent Application No. 11/634,343

(“the ’343 App.”) and which contains claims directed to aminoglycosides. Ex.

1003 (prosecution history of the ’845 Patent) at 107-118 (4/1/16 Non-Final Office

Action). The Examiner found the ’349 Patent “not patentably distinct” from the

then-pending claims of the ’845 Patent application, which were directed to

quinolones. Id. at 110. After submitting a 56 page information disclosure

statement identifying 716 references (see id. at 125-180 (5/19/16 IDS)), Patent

Owner submitted a response (see id. at 196-205 (5/20/16 Response)). To

overcome the double-patenting rejection, Patent Owner asserted that the then-

pending claims, which were directed to quinolones, and the claims of the ’349

Patent, which are directed to aminoglycosides, cover “distinct class[es] of

antiinfectives.” Id. at 201. The Examiner was persuaded by Patent Owner’s

assertion and withdrew the double patenting rejection; the Examiner acknowledged

that “[a]minoglycosides and fluoroquinolones are distinct classes of drugs and

would not be considered an [sic] obvious variants/substitutes.” Id. at 210-224

(5/27/16 Final Office Action) at 212-213 (emphasis added). Later, Patent Owner

again stated that aminoglycosides and quinolones are “unrelated.” Id. at 284-293

(6/9/16 Response) at 291.


30

62. With respect to the obviousness rejection, the Examiner asserted that

the pending claims were obvious over U.S. Patent No. 4,952,405 (“Yau-Young”)

in view of U.S. Patent Pub. No. 2004/0009126 (“Pilkiewicz”). Ex. 1003

(prosecution history of the ’845 Patent) at 107-118 (4/1/16 Non-Final Office

Action). As mentioned above, before responding to the Examiner’s obviousness

rejection, Patent Owner submitted a 56 page information disclosure statement

identifying 716 references. Id. at 125-180 (5/19/16 IDS). To overcome the

obviousness rejection, Patent Owner amended the claims to include the limitation

reciting the weight ratio range of free and encapsulated quinolone between 1:10

and 10:1; Patent Owner argued that Yau-Young and Pilkiewicz do not teach the

claimed weight ratio and do not teach immediate bactericidal activity. Id. at 284-

293 (6/9/16 Response). Patent Owner also submitted an affidavit from its expert,

Dr. Leserman; he attempted to show that the prior art Yau-Young formulation did

not have sufficient free ciprofloxacin to provide immediate bactericidal activity.

Dr. Leserman’s methodology (see id. at 304-311 (Dr. Leserman’s affidavit)) is

summarized as follows:

• Start with a 150 mg dose of liposomal ciprofloxacin;

• Determine how much of the initial dosage strength is delivered to the

lungs of the patient by assuming that 40% of the initially loaded

ciprofloxacin is delivered to the lungs;


31

• Multiply the dosage strength delivered to the lungs by 4% because

“free ciprofloxacin is rapidly diluted and cleared from the body” such

that “4% of the dose remained in the lungs”;

• Divide the prior answer (i.e., dosage strength delivered to the lungs

multiplied by 4%) by 14 mL or 20 mL, the volume of the airway

surface liquid (ASL) to get the concentration of ciprofloxacin in the

ASL;

• Compare the prior answers (i.e., concentrations of ciprofloxacin) to

the MIC values for ciprofloxacin in Ex. 1027 (Ciofu) at 4, Table 1

(emphasis added):

63. With that methodology, Dr. Leserman calculated that current claim 1

(at the low end of free ciprofloxacin—i.e., the 1:10 weight ratio of free to

liposome-encapsulated drug) results in 10.8 to 15.4 µg/mL of free ciprofloxacin in

the ASL. Ex. 1003 (prosecution history of the ’845 Patent) at 304-311 (Dr.

Leserman’s affidavit) at 309, ¶30. Dr. Leserman concluded that 10.8 to 15.4

µg/mL of free ciprofloxacin in the ASL was enough to “inhibit 50% of the

hypermutable strain” (with an MIC50 value of 12.5 µg/mL) and “90% of the


32

nonhypermutable” strain (with an MIC90 value of 6.2 µg/mL). Id. at 310, ¶¶33-34.

On the other hand, Dr. Leserman calculated that the prior art Yau-Young

formulation had between 3.0 and 4.3 µg/mL of free ciprofloxacin in the ASL. Id.

at 309, ¶29. Dr. Leserman concluded that 3.0 and 4.3 µg/mL of free ciprofloxacin

in the ASL “would not have been able to immediately provide a concentration of

free ciprofloxacin to inhibit 50% of the hypermutable strains” (with an MIC50

value of 12.5 µg/mL) and “at best” would not provide a concentration of free

ciprofloxacin to inhibit 90% of the nonhypermutable strains (with an MIC90 value

of 6.2 µg/mL). Id. at 30, ¶¶33-34. Notably, Dr. Leserman did not mention that the

prior art Yau-Young formulation does have sufficient free ciprofloxacin (3.0 and

4.3 µg/mL) to inhibit 50% of the nonhypermutable strains (with an MIC50 value of

1.6 µg/mL). Ex. 1027 (Ciofu) at 4, Table 1.

64. On June 23, 2016, the Examiner issued a notice of allowance. Ex.

1003 (prosecution history of the ’845 Patent) at 403-407 (6/23/16 Notice of

Allowability). The Examiner relied on Dr. Leserman’s affidavit as support for

why the “particular amount of free quinolone antibiotic in the liposomal

composition is important for practicing the claimed method of treatment.” Id. at

405. The Examiner also stated that Yau-Young and Pilkiewicz “suggest a free

antiinfective of about 2.5% by weight” but provide “no guidance … which would

suggest modifying the percentage of free antiinfective to at least 10% [sic] by


33

weight.” Id. Instead, Yau-Young and Pilkiewicz suggest “reduc[ing] the amount

of free drug in the liposomal preparation.” Id.

65. Dr. Leserman’s methodology is fundamentally flawed. First, there is

no support for Dr. Leserman’s assumption that “free ciprofloxacin is rapidly

diluted and cleared from the body” such that “4% of the dose remained in the

lungs.” Ex. 1003 (prosecution history of the ’845 Patent) at 304-311 (Dr.

Leserman’s affidavit) at 309, ¶26. Dr. Leserman incorrectly relies on Yim (Ex.

1003 (prosecution history of the ’845 Patent) at 391-394), which is irrelevant. In

Yim, the formulation was “intranasally instilled,” which means that the solution is

poured into the lungs. Id. at 392. Importantly, instillation does not reflect

inhalation. Even the FDA does not recognize instillation as a representative

model; during preclinical toxicology studies of aerosol antibiotics, FDA mandates

the use of aerosol administration, not instillation. Ex. 1051 (FDA)23 at 9 (“If a

drug substance in the new formulation has not been tested by inhalation, then

inhalation toxicity studies should be conducted,” not instillation toxicity studies)

(emphasis added). Another known problem with instillation is that it creates

23 “Nonclinical Safety Evaluation of Reformulated Drug Products and Products

Intended for Administration by an Alternate Route, Guidance for Industry and

Review Staff, Good Review Practice,” October 2015 (Ex. 1051).


34

“inhomogeneity of particle distribution” in the lungs. Ex. 1052 (Driscoll)24 at 5

(“Furthermore, with intratracheal instillation, macrophages at the lung periphery

contained few, if any, particles, and those cells in the regions of highest deposition

were overloaded, reflecting the inhomogeneity of particle distribution when the test

material was administered by instillation.”). Moreover, Yim’s instillation method

was performed on mice, and mouse physiology is not representative of human

physiology. The branching pattern of the airways in mice is monopodial (one main

stem) versus dichotomous (main stem bifurcates into two) in humans. Ex. 1053

(Hyde)25 at 2, Table I. The central airways of the mouse lung represent 11% of the

lung volume versus only 1% for that of humans, an eleven-fold difference between

species. Id. In humans, there are “[s]everal generations” of respiratory

bronchioles while in mice there are “[n]one or [one].” Id. Furthermore, there are

“substantial difference[s]” between the two species with respect to the amount of

epithelium that lines the trachea, with mice having one quarter to one sixth that of

24 Driscoll et al., “Intratracheal Instillation as an Exposure Technique for the

Evaluation of Respiratory Tract Toxicity: Uses and Limitations,” Toxicological

Sciences, 55, pp. 24-35 (2000) (Ex. 1052).

25 Hyde et al., “Anatomy, pathology, and physiology of the treacheobronchial tree:

Emphasis on the distal airways,” J. Allergy Clin. Immunol., Vol. 124, No. 6, pp.

S72-S77 (2009) (“Hyde”) (Ex. 1053).


35

humans. Ex. 1053 (Hyde) at 1 (“There is a substantial difference among species in

the amount of epithelium that lines the luminal surface in the trachea. The

thickness of the epithelium in the trachea of rhesus monkeys is approximately

twice that of mice and rats and one half to one third that of human subjects26.”)

(Emphasis added). The epithelium provides a barrier to absorption from the lung.

Because human lungs have more epithelium than mice lungs (i.e., 4 to 6 times

more), the mice lungs would have more rapid absorption. Accordingly, drugs will

clear out of a mouse’s lung at a different rate than for a human.

66. Second, Dr. Leserman improperly defines 15 minutes as

“immediately” after administration. Ex. 1003 (prosecution history of the ’845

Patent) at 304-311 (Dr. Leserman’s affidavit) at 309, ¶26. “Immediately” is time

zero, not after 15 minutes. At time zero, the proper amount of free drug is 100% of

free drug delivered to the lungs, because free drug will act immediately. Using

100% of the free drug in Yau-Young (1500 µg), the concentration of free

ciprofloxacin in the ASL is between 75.0 (1500 µg divided by 20 mL) and 107.1

26 The thickness of the epithelium in the trachea of mice/rats to rhesus monkeys to

humans is 2x:x:(1/2 to 1/3)x. Thus, between mice and humans, the difference in

the amount of epithelium that lines the trachea is 2x:(1/2 to 1/3)x or x:(1/4 to

1/6)x—i.e., mice have 1/4 or 1/6 of the amount of epithelium that lines the trachea,

as compared to humans.


36

µg/mL (1500 µg divided by 14 mL). Those amounts are well above the MIC50 and

MIC90 values for both nonhypermutable (1.6 and 6.2 µg/mL, respectively) and

hypermutable (12.5 and 25 µg/mL, respectively) isolates of Pseudomonas

aeruginosa. Ex. 1027 (Ciofu) at 4, Table 1. Even if only half of the free drug is

available (750 µg), the concentration of free ciprofloxacin in the ASL is between

37.5 (750 µg divided by 20 mL) and 53.6 µg/mL (750 µg divided by 14 mL); that

range is still well above the MIC50 and MIC90 values for both nonhypermutable

(1.6 and 6.2 µg/mL, respectively) and hypermutable (12.5 and 25 µg/mL,

respectively) isolates of Pseudomonas aeruginosa.

67. Third, for his calculations, Dr. Leserman selected two populations of

Pseudomonas aeruginosa, one of which (hypermutable) is highly resistant to

ciprofloxacin. Ex. 1003 (prosecution history of the ’845 Patent) at 304-311 (Dr.

Leserman’s affidavit) at 310, ¶33; Ex. 1027 (Ciofu) at 4, Table 1 (MIC50 and

MIC90 values for the hypermutable isolate of Pseudomonas aeruginosa is 12.5 and

25 µg/mL, respectively). But that is not representative of Pseudomonas

aeruginosa. Zhanel performed a “critical review of the fluoroquinolones.” Ex.

1026 (Zhanel) at Title. Zhanel determined MIC50 and MIC90 values for

ciprofloxacin against Pseudomonas aeruginosa by gathering the most recently

reported values in reports primarily from 1998 until 2002 (when Zhanel was

published). Id. at 10 (“The MIC values provided in the tables were gathered from


37

the review and synthesis of the most recently reported values for each drug. An

attempt was made to focus primarily on reports from 1998 until the present, but

where this span was inadequate for a complete report of the drug’s antibacterial

activity, earlier studies were reviewed and included where deemed appropriate.”).

Zhanel reported MIC50 and MIC90 values for ciprofloxacin against Pseudomonas

aeruginosa as 0.25 and 4 µg/mL, respectively. Those values are much lower than

the values reported in Ciofu, especially the hypermutable isolate (MIC50 of 12.5

and MIC90 of 25 µg/mL). Id. at 12; Ex. 1027 (Ciofu) at 4, Table 1. An abbreviated

version of the table is reproduced below:

Source: Ex. 1026 (Zhanel) at 12.

68. In fact, as taught by Saiman, as discussed below, as little as 2 µg/mL

of ciprofloxacin treated nearly 80% of the strains from patients with Pseudomonas

aeruginosa. Ex. 1025 (Saiman) at 2, 3. Saiman received and tested 1,296 strains

of Pseudomonas aeruginosa taken from CF patients with Pseudomonas aeruginosa

from 67 centers in 31 states. Id. at 1. Saiman found that with as little as 2 µg/mL

of ciprofloxacin, 21% of the 1,296 strains were resistant to ciprofloxacin. Id. at 2,


38

3. That translates to a concentration of 2 µg/mL effectively treating 79% of the

strains from patients with Pseudomonas aeruginosa.

69. Dr. Leserman determined that the amount of free ciprofloxacin in

Yau-Young was between 3.0 and 4.3 µg/mL. Ex. 1003 (prosecution history of the

’845 Patent) at 304-311 (Dr. Leserman’s affidavit) at 309, ¶29. Notably, that

amount is above the 2 µg/mL concentration that treated 79% of the strains from

patients with Pseudomonas aeruginosa in Saiman. Ex. 1025 (Saiman) at 2, 3. In

other words, the amount of free drug disclosed in Yau-Young (even based on Dr.

Leserman’s flawed methodology) is more than sufficient to provide immediate

bactericidal activity against nearly 80% of the Pseudomonas aeruginosa strains

and would have treated nearly 80% of the strains from patients with Pseudomonas

aeruginosa. In addition, the amount of free ciprofloxacin in Yau-Young (3.0 and

4.3 µg/mL), as determined by Dr. Leserman, is above the MIC50 and MIC90 values

(0.25 and 4 µg/mL, respectively) reported in Zhanel’s comprehensive report. Ex.

1026 (Zhanel) at 12. In the proper context, a POSITA understands that Yau-

Young does have sufficient free ciprofloxacin to provide immediate bactericidal

activity against Pseudomonas aeruginosa.

70. Fourth, Dr. Leserman chose a 150 mg initial dose for his calculations

in order to generate final concentrations of free ciprofloxacin in Yau-Young that

were low. Dr. Leserman chose 150 mg from a liposomal ciprofloxacin formulation


39

under development by Aradigm. Ex. 1003 (prosecution history of the ’845 Patent)

at 304-311 (Dr. Leserman’s affidavit) at 307-308, ¶¶17, 18. But it was known that

Aradigm also investigated dosage strengths up to 450 mg. Ex. 1054

(Bruinenberg)27 at 3 (“This was an open-label, dose-escalation study to evaluate

the safety, tolerability, and pharmacokinetics of 3 mL (150 mg), 6 mL (300 mg),

and 9 mL (450 mg) of 50 mg/mL CFI (11)”) (emphasis added). Had Dr. Leserman

chose a 450 mg initial dose, then the free ciprofloxacin concentrations would have

been three times higher than with the 150 mg initial dose Dr. Leserman relied on.

With the 450 mg initial dose, the Yau-Young formulation results in a concentration

of free ciprofloxacin in the ASL of between 9.0 and 12.9 µg/mL. Those

concentrations are above the MIC50 and MIC90 values of the nonhypermutable

isolate (1.6 and 6.2 µg/mL, respectively) and above the MIC50 value of the

hypermutable isolate (12.5 µg/mL). Those results (9.0 and 12.9 µg/mL) are similar

to the claimed invention (10.8 and 15.4 µg/mL), which according to Dr. Leserman,

is sufficient to provide immediate bactericidal activity. Ex. 1003 (prosecution

history of the ’845 Patent) at 304-311 (Dr. Leserman’s affidavit) at 310, ¶¶33-34.

27 Bruinenberg et al, “Inhaled Liposomal Ciprofloxacin: Once a Day Management

of Respiratory Infections,” Respiratory Drug Delivery 2010, pp. 73-82 (2010)

(“Bruinenberg”) (Ex. 1054).


40

VIII. LEVEL OF ORDINARY SKILL IN THE ART

71. I have been informed by counsel and I understand that the ’845 Patent

was filed on January 4, 2016, but that it claims an earliest possible priority date of

December 8, 2005, based on the filing date of the ’468 Provisional. Ex. 1001 (’845

Patent). I have been instructed by counsel that, for purposes of this Declaration

only, the invention date of any claims of the ’845 Patent that are properly

supported by the ’468 Provisional would be December 8, 2005.

72. I have been informed by counsel and I understand that the ’845 Patent

is part of a chain of non-provisional applications, all claiming priority back to the

’468 Provisional. Ex. 1001 (’845 Patent) at 1, (63). The first non-provisional

application, the ’343 App., was filed on December 5, 2006, and issued as U.S.

Patent No. 8,226,975. Ex. 1007 (’343 App.). The second non-provisional

application, U.S. Patent Application No. 13/527,213 (“the ’213 App.”), is listed as

a continuation of the ’343 App., was filed on June 19, 2012, and issued as U.S.

Patent No. 8,632,804. Ex. 1008 (’213 App.). The third non-provisional


a continuation of the ’213 App., was filed on November 1, 2012, and issued as

U.S. Patent No. 8,642,075. Ex. 1009 (’420 App.). The fourth non-provisional


a continuation of the ’420 App., was filed on November 15, 2013, and is still


41

pending. Ex. 1010 (’922 App.). Finally, the application issuing as the ’845 Patent

(U.S. Patent Application No. 14/987,508), is listed as a continuation of the’922

App., and was filed January 4, 2016. Ex. 1001 (’845 Patent).

73. The ’845 Parent Apps. (i.e., the ’343, ’213, ’420, and ’922 Apps.) and

the ’845 Patent form a chain of continuations; they share the same patent

specification except for the portions reciting “Related Applications.” Furthermore,

the ’845 Parent Apps., the ’845 Patent, and the ’468 Provisional share the same

disclosure, except for the portions reciting “Related Applications” (the ’468

Provisional does not have a “Related Applications” section because it was the first

in the chain).

74. Unlike the ’845 Parent Apps. (i.e., the ’343, ’213, ’420, and ’922

Apps.) which have claims directed to aminoglycosides, the claims of the ’845

Patent are directed to a distinct class of antiinfectives, quinolones.

75. With respect to whether the claims of the ’845 Patent are enabled by,

or supported by the written description of, a particular application, I have been

instructed by counsel to consider those issues with respect to the state of the art as

of the actual filing date of the particular application. Whether the claims of the

’845 Patent are enabled by, or supported by the written description of, the ’845

Parent Apps. and the ’468 Provisional, is to be considered in view of the state of

the art as of the filing dates of those applications (December 8, 2005 through


42

November 15, 2013). Whether the claims of the ’845 Patent are enabled by, or

supported by written description of, the ’845 Patent itself, is to be considered in

view of the state of the art as of January 4, 2016, the actual filing date of the ’845

Patent.

76. Because it is my opinion that (1) claims 1-26 are not enabled by the

’845 Parent Apps. or the ’468 Provisional, and (2) claims 1-26 lack adequate

written description in the ’845 Parent Apps. or the ’468 Provisional, I have been

instructed by counsel to also consider an alternative priority date of January 4,

2016 (the actual filing date of the ’845 Patent) with respect to claims 1-26.

77. I have been informed by counsel and I understand that the POSITA is

a hypothetical person who is presumed to be familiar with the relevant scientific

field and its literature at the time of the invention. I additionally understand that

this hypothetical person is a person of ordinary creativity in his or her field. The

POSITA is assumed to be aware of all relevant prior art at the time an invention

took place. The POSITA is also capable of understanding the scientific principles

applicable to the pertinent field and able to fit the teachings of multiple prior art

references together like pieces of a puzzle.

78. I am informed by counsel and I understand that the level of ordinary

skill in the art may be determined by reference to certain factors, including (1) the

educational level of the inventor, (2) the type of problems encountered in the art,


43

(3) prior art solutions to those problems, (4) the rapidity with which innovations

are made, (5) the sophistication of the technology, and (6) the educational level of

active workers in the field.

79. It is my opinion that the claims of the ’845 Patent are generally

directed to methods of treating pulmonary infections using aerosolized

formulations. In my opinion, a POSITA would have been an individual or team

with an advanced degree (such as an M.D. or Ph.D.) in the field of molecular

biology, biochemistry, microbiology, engineering, or a related field and one to two

years of post-graduate experience with a focus on aerosolized delivery of

medication.

IX. CLAIM CONSTRUCTION

80. I have been informed by counsel and I understand that, in post grant

and inter partes review proceedings, claims of unexpired patents are construed

under the “broadest reasonable interpretation” standard. Under this standard,

claims are construed according to their broadest reasonable construction in light of

the specification as it would be interpreted by a POSITA at the time of the

invention.

81. I have been informed by counsel and I understand that, if the patentee

has acted as her own lexicographer and has clearly defined a claim term in the

patent specification, that definition is applied.


44

82. I have been informed by counsel and I understand that a patentee’s

arguments during prosecution will only operate to limit the patent claims if there

was a clear and unambiguous disavowal of scope by the patentee.

A. Claim Terms Requiring Construction

1. “pharmaceutical formulation comprising a mixture of free quinolone antibiotic agent, a quinolone antibiotic agent encapsulated in a plurality of liposomes”

83. Claim 1 of the ’845 Patent recites a “pharmaceutical formulation

comprising a mixture of free quinolone antibiotic agent, a quinolone antibiotic

agent encapsulated in a plurality of liposomes.” Ex. 1001 (’845 Patent) at claim 1.

In my opinion, the broadest reasonable interpretation of the term “pharmaceutical

formulation comprising a mixture of free quinolone antibiotic agent, a quinolone

antibiotic agent encapsulated in a plurality of liposomes” is “pharmaceutical

formulation comprising a pre-nebulized or post-nebulized mixture of free

quinolone antibiotic agent, a quinolone antibiotic agent encapsulated in a plurality

of liposomes.”

84. This construction is consistent with the specification of the ’845

Patent, which states:

Combinations of free and encapsulated drug can be

achieved by: (a) formulation of mixtures of free and

encapsulated drug that are stable to the nebulization; (b)


45

formulation of encapsulated drug which leads to burst on

nebulization.

Ex. 1001 (’845 Patent) at 2:63-67. A POSITA understands that a “formulation of

mixtures of free and encapsulated drug that are stable to the nebulization” means a

pre-nebulized formulation of free and liposome-encapsulated drug. Id. (emphasis

added). It was well known that nebulization can disrupt (e.g., break open, rupture,

or cause leakage) liposomes, thereby causing encapsulated drug to be released as

free or unencapsulated drug. Ex. 1044 (Niven) at Abstract (“In all experiments[,

the liposome-encapsulated drug] was released from the liposomes while being

aerosolized …”), 4 (“For all liposome compositions tested[,] there was a release of

encapsulated [drug] to the surrounding buffer solution during nebulization.”).

Indeed, the inventor of the ’845 Patent acknowledges the fact that “[l]iposomal

preparations of amikacin may exhibit significant leakage of encapsulated drug

during nebulization.” Ex. 1001 (’845 Patent) at 14:11-12. Liposomes that are

“stable to the nebulization” are liposomes that minimize leakage of encapsulated

drug upon nebulization. Id. at 2:63-67. Accordingly, to achieve a combination of

free drug and encapsulated drug stable to nebulization, the ’845 Patent teaches that

the pre-nebulized formulation should contain some free drug.

85. In addition, a POSITA understands that a “formulation of

encapsulated drug which leads to burst on nebulization” means a formulation that

results in free and liposome-encapsulated drug, after nebulization—in other words,


46

the post-nebulized formulation contains free and liposome-encapsulated drug. Id.

(emphasis added). As mentioned above, it was well known that nebulization can

disrupt the liposomes, causing leakage of drug from liposomes. The ’845 Patent

teaches that to achieve a combination of free and encapsulated drug, a POSITA can

start with a formulation (i.e., pre-nebulized) of liposome-encapsulated drug—with

no free drug—because upon nebulization (post-nebulized), some of those

liposomes are disrupted (e.g., “burst”) and release the encapsulated drug as free or

unencapsulated drug. Ex. 1044 (Niven) at Abstract (“In all experiments[, the

liposome-encapsulated drug] was released from the liposomes while being

aerosolized …”), 4 (“For all liposome compositions tested[,] there was a release of

encapsulated [drug] to the surrounding buffer solution during nebulization.”); Ex.

1001 (’845 Patent) at 2:63-67.

86. This construction is also consistent with the only two examples in the

’845 Patent. In Example 1, “[t]he nebulized liposomal amikacin contains a

mixture of encapsulated (ca., 60%) and free amikacin (ca., 40%).” Ex. 1001 (’845

Patent) at 13:42-43 (emphasis added). That post-nebulization formulation is the

basis for lone Figure 1, which purportedly shows the “presence of free and

encapsulated antiinfective in the amikacin formulation” and “improved lung

targeting afforded by liposomal encapsulation.” Id. at 13:56-60. In Table 1 of


47

Example 2, there are two formulations (A and B), both of which contain pre- and

post-nebulized formulations of free and encapsulated drug.

Id. at 14:25-36.

X. EFFECTIVE FILING DATES OF THE CLAIMS OF THE ’845 PATENT

87. I have been informed by counsel and I understand that the “effective

filing dates” of the claims of the ’845 Patent dictate (1) whether the ’845 Patent is

a “post-AIA” patent that is eligible for review in the present PGR proceeding, and

(2) the time frame of the relevant prior art (and the state of the art).

88. I have been informed by counsel and I understand that the “effective

filing date” of a patent claim is the patent’s actual filing date, unless the patent

properly claims priority (or the benefit of an earlier filing date) from a parent

application that discloses the claimed invention in compliance with the written

description and enablement requirements.


48

89. I have been informed by counsel and I understand that, to satisfy the

enablement requirement, the specification must enable a POSITA, as of the filing

date, to practice the full scope of the claims without “undue experimentation.” I

understand that relevant factors in assessing whether undue experimentation would

be necessary include:

(1) the quantity of experimentation necessary, (2) the amount of

direction or guidance presented, (3) the presence or absence of

working examples, (4) the nature of the invention, (5) the state of the

prior art, (6) the relative skill of those in the art, (7) the predictability

or unpredictability of the art, and (8) the breadth of the claims.

I also understand, however, that the above factors are illustrative, not mandatory,

and that what is relevant depends on the particular facts of the case.

90. To comply with the written description requirement, I have been

informed by counsel and I understand that the specification must reasonably

convey to a POSITA that the inventor had possession of the claimed subject matter

as of the filing date. I also understand that a description that merely renders the

invention obvious does not satisfy the requirement. I also understand that “laundry

list” disclosures of every possible species in a genus are often inadequate to

disclose a particular species within that genus. In such cases, I have been informed

by counsel that to satisfy the written description requirement, the specification

must contain “blaze marks” directing a POSITA to that particular species.


49

A. The ’845 Patent Is a Post-AIA Patent Eligible for PGR

91. I have been informed by counsel and I understand that, to be eligible

for PGR, a threshold requirement is that the patent must have at least one claim

with an “effective filing date” that is on or after March 16, 2013 (the earliest date

for PGR eligibility).

92. The ’845 Patent was filed on January 4, 2016. Ex. 1001 (’845 Patent)

at 1, (22). The ’845 Patent claims priority from several non-provisional

applications (sharing the same disclosure as the ’845 Patent) and the ’468

Provisional. Exs. 1002, 1007-1010. As discussed above in ¶73, the ’845 Parent

Apps. and the ’468 Provisional share the same substantive disclosure. However, in

my opinion, the ’845 Parent Apps. and the ’468 Provisional do not enable the full

scope of claims 1-26. Moreover, the ’845 Parent Apps. and the ’468 Provisional

do not provide written description of the subject matter of claims 1-26. The above

claims are not entitled to the benefit of the filing date of any of the ’845 Parent

Apps. or the ’468 Provisional; instead, the effective filing date is the actual filing

date of the ’845 Patent, January 4, 2016.

1. The effective filing date of claims 1-26 is the actual filing date of the ’845 Patent, because the ’845 Parent Apps. and the ’468 Provisional do not enable the full scope of the claims

93. The specifications of the ’845 Parent Apps. and the ’468 Provisional

do not enable a POSITA to make and use, without undue experimentation, the


50

alleged pharmaceutical formulation comprising free and liposome-encapsulated

quinolone.

94. As discussed above in ¶73, the ’845 Parent Apps. and the ’468

Provisional share the same substantive disclosure. The ’845 Parent Apps. and the

’468 Provisional only disclose quinolone as one of many antiinfective agents

known to exist. Ex. 1001 (’845 Patent) at 3:10-19; 4:4-13; 9-19-26. There are no

quinolone-specific embodiments in the specification. There are no examples of

any quinolone-containing formulations. The only two examples in the patent are

directed to formulations of liposomal amikacin—an aminoglycoside, not a

quinolone. During prosecution, Patent Owner repeatedly acknowledged that

aminoglycosides and quinolones are “distinct class[es] of antiinfectives” and

“unrelated” to each other. Ex. 1003 (prosecution history of the ’845 Patent) at

196-205 (5/20/16 Response) at 201; id. at 284-293 (6/9/16 Response) at 291. And

the Examiner relied on Patent Owner’s statement to withdraw the double-patenting

rejection. Id. at 210-224 (5/27/16 Final Office Action) at 213 (“[a]minoglycosides

and fluoroquinolones are distinct classes of drugs and would not be considered an

[sic] obvious variants/substitutes”) (emphasis added).

95. Quinolones and aminoglycosides are distinct. They have very

different chemical structures (e.g., aminoglycosides comprise a sugar core while

quinolones comprise a bicyclic core where one of the rings contain nitrogen):


51

Aminoglycosides Quinolones

Tobramycin

General structure

Amikacin

Ciprofloxacin

Sisomicin

That chemical distinctness results in different chemical properties.

96. For example, amikacin (a type of aminoglycoside) and ciprofloxacin

(a type of quinolone) are distinct antibiotics with distinct properties. Amikacin is

extremely water soluble (185 mg/mL), but ciprofloxacin is not (<0.1 mg/mL and

up to about 30 mg/mL, with a 0.3 mg/mL solubility at pH 6). Ex. 1038 (Drug

Bank for amikacin) at 7; Ex. 1039 (Drug Bank for ciprofloxacin) at 12; Ex. 1040

(Yu) at 3, Figure 3; Ex. 1037 (Cullis 1989) at 10 (“extremely water soluble (e.g.,

100 mg/ml)”). In fact, amikacin is nearly seven orders of magnitude more


52

hydrophilic than ciprofloxacin. Compare Ex. 1038 (Drug Bank for amikacin) at 7

and Ex. 1039 (Drug Bank for ciprofloxacin) at 12 (amikacin has a logP value of -

7.4 and ciprofloxacin has a logP value of 0.28). Because of amikacin’s high water

solubility, as discussed above, passive loading is an acceptable method for loading

amikacin into liposomes. In contrast, ciprofloxacin is the least soluble in water

around physiological pH, and a poor candidate for passive loading/trapping.

Ex. 1040 (Yu) at 3, Figure 3.

97. Instead, to load ciprofloxacin into liposomes at physiological pH, a

POSITA would have to create and use an active loading/trapping method. But the

’845 Parent Apps. and the ’468 Provisional do not mention—let alone teach a

POSITA—how to load ciprofloxacin, or any other quinolone, into liposomes.

98. The ’845 Parent Apps. and the ’468 Provisional also do not disclose

any liposomes suitable for quinolones. Nor do they teach how to make a mixture

of free and liposome-encapsulated quinolones that provide both immediate and


53

sustained bactericidal activity. In fact, the ’845 Parent Apps. and the ’468

Provisional do not even describe how to make the formulations of free and

liposome-encapsulated amikacin discussed in Examples 1 and 2. There is no “one-

size-fits-all” liposome that is optimal for all types of drug. Liposomes must be

tailored to the unique characteristics of the drug ingredient or the loading method if

active loading is needed. Ex. 1044 (Niven) at Abstract (for the same drug,

different lipid compositions had very different effects on the release of liposome-

encapsulated drug from liposomes—between “12.7 ± 3.8 to 60.9 ±1.9% of the

encapsulated [drug]”), 6 (factors affecting the retention of drug in liposomes are

“vesicle size, the operating characteristics of the nebulizer system, and the

physicochemical characteristics of the drug in question”).

99. I also reviewed the patents and patent publications that were

incorporated by reference into the specification. Those references merely disclose

generic methods of preparing liposomes; they do not teach or describe how to

make the claimed pharmaceutical formulations of free and liposome-encapsulated

quinolone. I have also reviewed the non-patent publications incorporated by

reference into the specification28. I have been informed by counsel that such

28 I reviewed the following five non-patent publications: (1) “Schentag, J.J. J.

Chemother. 1999, 11, 426-439” (Ex. 1001 (’845 Patent) at 3:8-9); (2) “Deamer and

Uster (1983)” (id. at 8:3); (3) “Bangham et al. (J. Mol. Biol., 1965, 13:238-252)”


54

publications cannot provide enablement or written description support.

Nevertheless, like the patents and patent publications, these non-patent

publications do not teach how to make the claimed pharmaceutical formulations of

free and liposome-encapsulated quinolone.

100. With so little guidance, a POSITA would have to carry out an undue

amount of experimentation to make the pharmaceutical formulation of free and

liposome encapsulate quinolone as recited in claim 1 and dependent claims 18-23,

and 25-26. For example, a POSITA would need to research which liposomes,

including the underlying lipids, would be suitable for quinolones. He/she would

also need to determine which drug loading/trapping method is suitable for a

particular quinolone and liposome. He/she would also need to determine

acceptable drug to lipid ratios and acceptable lipid ratios in the liposome (e.g., lipid

to cholesterol ratios). He/she would also need to conduct in vitro and in vivo tests

to determine whether the liposomes have integrity to provide sustained bactericidal

(id. at 8:4-5); (4) “Papahadjopoulos et al. (Biochim. Biophys, Acta., 1967,

135:624-638)” (id. at 8:14-15); and (5) “Szoka, Jr. et al., (1980, Ann. Rev.

Biophys. Bioeng., 9:467)” (id. at 8:23-24). I did not review the following three

non-patent publications because I could not decipher the citation: (1) “Cullis et al.

(1987)” (id. at 7:54); (2) “Paphadjopoulos et al. (1968)” (id. at 8:2); (3) “Chapman

et al. (1968) (id. at 8:3).


55

activity. To be an approved pharmaceutical product, one has to demonstrate

stability data over the time period one wants for shelf life, typically at least a year,

and usually two years. A POSITA also needs to control the amount of free and

liposome-encapsulated quinolone in the original composition before nebulization,

and understand how nebulization would affect the amount of free and liposome-

encapsulated quinolone, to achieve the right amount of drug to provide immediate

and sustained bactericidal activity. He/she would also need to conduct tests in cell-

based assays, on animals and/or humans to demonstrate both immediate and

sustained release efficacy. Liposomes, when deposited in the lung by aerosol can

cause local toxicity; thus, animal toxicology studies would be needed before any

human testing.

101. This is not routine experimentation. This is true even now. As a real-

world example, to develop a liposome-encapsulated ciprofloxacin formulation,

Aradigm engaged in extensive research and development. Aradigm investigated

various combinations of four types of lipid and cholesterol. Ex. 1055 (Cipolla

2016)29 at 4 (“choice of lipid (egg sphingomyelin (ESM), hydrogenated soy

phosphatidylcholine (HSPC), egg phosphatidylcholine (EPC) and 1-palmitoyl-2-

oleoylphosphatidylcholine (POPC))”). Aradigm also investigated four types of

29 Cipolla et al., “Development of Liposomal Ciprofloxacin to Treat Lung

Infections,” pharmaceutics, 8(1), 6 (March 1, 2016) (“Cipolla 2016”) (Ex. 1055).


56

loading agents suitable to actively load ciprofloxacin into liposomes. Id. (“choice

of loading agent (methylamine sulfate, magnesium sulfate, ammonium sulfate and

ferrous sulfate)”). With just one lipid and cholesterol for each loading agent, there

are 16 possible combinations of lipid, cholesterol, and loading agent. But Aradigm

also investigated various “drug to lipid” and “lipid to cholesterol” ratio. Id. Those

“various liposome compositions were evaluated by both in vitro and in vivo

methods” for:

• “acceptable long term refrigerated stability”;

• “drug release consistent with once-daily dosing”;

• “retention of liposome integrity during storage and aerosol delivery”;

and

• “a robust manufacturing process.”

Ex. 1055 (Cipolla 2016) at 4 (emphasis added).

102. The in vivo tests were conducted on mice and rabbits. Ex. 1055

(Cipolla 2016) at 4. Aradigm tested various liposome compositions in mice to

determine which liposome compositions had adequate, sustained levels of

ciprofloxacin for 24 hours. Ex. 1055 (Cipolla 2016) at 4-5. Aradigm also tested

various liposome compositions in rabbits to determine the half-lives (the amount of

time to remove half of the liposome-encapsulated drug) of aerosolized liposome

compositions. Id. at 4 (ranging from 8.3 to 10.2 hours in the lung tissue and 13.4


57

hours in plasma). To assess retention of the functional properties of the liposome-

encapsulated ciprofloxacin formulations upon nebulization, Aradigm conducted

additional experiments by depositing aerosolized liposome-encapsulated

ciprofloxacin directly onto Calu-3 cells, which are cells with similar characteristics

to human epithelium cells lining the airways. Id. at 9, 10, Fig. 7.

103. Aradigm also conducted nebulization stability tests. One batch was

subjected to nebulization stability testing after 3 and 6 months of storage at room

temperature. Ex. 1055 (Cipolla 2016) at 7-8, Table 1. A second batch was

subjected to nebulization stability testing after 3, 6, 9, 12, 18, and 24 months of

storage at refrigerated temperatures. Id. Ten subsequent batches were subjected to

nebulization stability testing after 24 months of storage at refrigerated

temperatures. Id. at 7-8, Tables 1 and 2. Demonstrating stability data over two

years reflects the fact that two years is the typical time period one wants for shelf

life.

104. Aradigm also conducted “[e]xtensive preclinical safety studies” (in

vivo and in vitro) in rats and dogs and against various infective agents, such as

Pseudomonas aeruginosa, Mycobaterium avium, Mycobacterium abscessus,

Francisella tularensis, Yersinia pestis, and Coxiella burnetti. Ex. 1055 (Cipolla

2016) at 11-14. Currently, Aradigm’s product is in clinical trials in humans.


58

105. I have been involved in the development of three aerosolized FDA-

approved drugs for pulmonary infection and am well aware of the difficulties and

uncertainties of drug development in this field. Aerosolized liposomal

pharmaceutical formulation work is tailored for the unique characteristics of the

drug. A POSITA would understand that a liposome suitable for encapsulating one

compound (e.g., amikacin) in one class of drugs (e.g., aminoglycoside) will not

necessarily be suitable for encapsulating another compound (e.g., ciprofloxacin) in

a completely distinct class of drugs (e.g., quinolone).

106. Since a POSITA would have to carry out an undue amount of

experimentation to make the broad pharmaceutical formulation of free and

liposome-encapsulated quinolone as recited in independent claim 1, he/she would

also require undue experimentation to make the specific pharmaceutical

formulations of dependent claims 2-26.

2. The effective filing date of claims 1-26 is the actual filing date of the ’845 Patent, because the ’845 Parent Apps. and the ’468 Provisional lack written description of the broadly-claimed subject matter

107. The specifications of the ’845 Parent Apps. and the ’468 Provisional

provide no written description of pharmaceutical formulations with free and

liposome-encapsulated quinolone, let alone a method for treating a pulmonary

infection using such pharmaceutical formulations in aerosolized form to provide

immediate and sustained bactericidal activity. As discussed above in ¶73, the ’845


59

Parent Apps. and the ’468 Provisional share the same substantive disclosure. The

’845 Parent Apps. and the ’468 Provisional only disclose quinolone as one of the

many antiinfective agents known to exist. Ex. 1001 (’845 Patent) at 3:10-19, 4:4-

13, 9-19-26. There are no quinolone embodiments in the specification. There are

no examples of any quinolone-containing formulations. The only two examples in

the patent are directed to formulations of liposomal amikacin, which is a member

of a “distinct class of antiinfectives” and “unrelated” to quinolones. Ex. 1003

(prosecution history of the ’845 Patent) at 196-205 (5/20/16 Response) at 201; id.

at 284-293 (6/9/16 Response) at 291.

108. As discussed above, I have also reviewed the references that were

incorporated by reference into the specification. For the reasons discussed above

in ¶99 and in footnote 28, those references do not provide written description

support for the quinolone pharmaceutical formulations for treating pulmonary

infections recited in claim 1, let alone the more detailed formulations and

pulmonary infections recited in dependent claims 2-26.

109. In sum, the scant disclosure of the ’845 Patent would not have guided

a POSITA to the quinolone pharmaceutical formulations for treating pulmonary

infections recited in claim 1, let alone the more detailed formulations and

pulmonary infections recited in dependent claims 2-26.


60

XI. NON-ENABLEMENT ANALYSIS

A. Claims 1-26 Are Invalid for Nonenablement

110. As detailed above, at least claims 1-26 were not enabled as of the

filing dates of the ’845 Parent Apps. and the ’468 Provisional. Those claims were

likewise not enabled by the specification of the ’845 Patent as of its filing date

(January 4, 2016). Therefore, it is my opinion that the claims are invalid.

111. The non-provisional ’845 Parent Apps. (Exs. 1007-1010) and the ’468

Provisional (Ex. 1002) share the same disclosure as the ’845 Patent (Ex. 1001).

Thus, the ’845 Patent does not teach anything more than the ’845 Parent Apps. and

the ’468 Provisional. For the same reasons provided above in ¶¶93-106, a

POSITA would have required undue experimentation to make the pharmaceutical

formulation of free and liposome encapsulate quinolone as recited in claims 1-26.

XII. LACK OF WRITTEN DESCRIPTION ANALYSIS

A. Claims 1-26 Are Invalid for Lack of Written Description

112. As detailed above, at least claims 1-26 lack written description

support as of the filing dates of the ’845 Parent Apps. and the ’468 Provisional.

Those claims likewise lack written description support as of the ’845 Patent’s

filing date (January 4, 2016). Therefore, it is my opinion that the claims are

invalid.

113. The non-provisional ’845 Parent Apps. (Exs. 1007-1010) and the ’468

Provisional (Ex. 1002) share the same disclosure as the ’845 Patent (Ex. 1001).


61

Thus, the ’845 Patent does not teach anything more than the ’845 Parent Apps and

the ’468 Provisional. For the same reasons provided above in ¶¶107-109, a

POSITA would not have been guided to the quinolone pharmaceutical

formulations for treating pulmonary infections recited in claim 1, let alone the

more detailed formulations and pulmonary infections recited in dependent claims

2-26.

XIII. SUMMARY OF PRIOR ART REFERENCES

A. Finlay

114. I have been informed by counsel and I understand that Finlay (Ex.

1024), published on or about June 1, 1998, is prior art. Finlay is entitled “Regional

lung deposition of nebulized liposome-encapsulated ciprofloxacin.” Finlay loaded

a formulation of free and liposome-encapsulated ciprofloxacin into five different

nebulizers and assessed how much ciprofloxacin was inhaled when delivered by

those five different nebulizers.

115. Prior to Finlay, the “concept of encapsulating therapeutic agents

inside liposomal vesicles to enhance their effectiveness in the treatment of

respiratory disease by aerosol inhalation” was known. Ex. 1024 (Finlay) at 1-2.

But Finlay acknowledges that while “nebulization is often the easiest method of

delivery from a formulation point of view,” several factors contribute to the

uncertainty of drug delivery by nebulization. Id. at 2. “Two such factors include


62

disruption of liposomes by nebulization … as well as uncertainty in the amount of

encapsulated drug that different nebulizer models will deliver to different regions

of the lung with a given formulation.” Id. Those two factors are “formulation

specific, making it difficult to predict the behaviour of a new formulation from

previous results.” Id.

116. Finlay reports that “[r]ecent studies have shown that liposome-

encapsulated ciprofloxacin is significantly more effective than free

(unencapsulated) ciprofloxacin in the prevention and treatment of intracellular

bacterial infections of the respiratory tract in mice.” Id. at 2. Accordingly, “an

effective means of delivering liposome-encapsulated ciprofloxacin is needed.” Id.

117. Finlay discloses pharmaceutical formulations of “[l]iposome-

encapsulated ciprofloxacin” and free ciprofloxacin that were nebulized in five

different nebulizers (LC STAR, LC+, Sonix 2000, T-Updraft II, and Permaneb) to

test, among other things, how much ciprofloxacin (both free and liposome-

encapsulated) would be inhaled by a patient. Id.

118. Finlay’s liposomes encapsulating ciprofloxacin are unilamellar

vesicles that were extruded through a 0.2 µm30 pore size filter. Ex. 1024 (Finlay)

30 I note that there is a typographical error in Finlay. Finlay’s pore size filter is 0.2

microns (µm), not millimeters. Finlay discloses that its “[l]iposomal-encapsulated

ciprofloxacin was prepared using a modification of the remote loading procedure


63

at 2. Accordingly, Finlay’s liposomes are about 0.2 microns in diameter. Finlay’s

liposomes “consisted of a 55:45 molar ratio of

phospahtidylcholine[sic]/cholesterol.” Id. “A concentration of 22.2 mg liposome-

encapsulated-ciprofloxacin/ml in normal saline was used for the nebulization in

this study.” Id. Finlay’s formulation contained “90 ± 2%” of ciprofloxacin

entrapped in liposomes and 10 ± 2% of free ciprofloxacin. Id.

of Oh et al. (1995),” with liposomes that are “[u]nilamellar vesicles.” Ex. 1024

(Finlay) at 2. In Oh (Ex. 1056), the liposomal ciprofloxacin was prepared “by

modifying a remote-loading technique developed for doxorubicin” and “extruded

… through a 0.2-µm-pore-size polycarbonate membrane filter.” Oh et al.,

“Formulation and Efficacy of Liposome-Encapsulated Antibiotics for Therapy of

Intracellular Mycobacterium avium Infection,” Antimicrobial Agents and

Chemotherapy, Vol. 39, No. 9, pp. 2104-2111 (September 1995) (Ex. 1056) at 2

(emphasis added). Because Finlay used the same loading procedure as Oh, Finlay

would also have used a 0.2 micron (µm) pore size filter. Furthermore, the 0.2 mm

filter in Finlay is obviously a typographical error. 0.2 mm is 200 microns, which is

1,000 times larger than 0.2 microns. A POSITA knows that unilamellar vesicles

range between about 50 nm (0.05 microns) and about 200 nm (0.2 microns). Ex.

1035 (Cullis 1987) at 7.


64

119. Finlay’s formulation of “90 ± 2%” of liposome-encapsulated

ciprofloxacin and 10 ± 2% of free ciprofloxacin was nebulized in five nebulizers;

the total amount of inhaled ciprofloxacin (as a % of the initial dose placed in the

nebulizer) are detailed below:

Ex. 1024 (Finlay) at 2, 5, Figure 2.

120. Finlay reports that “the ratio, x, of free to encapsulated ciprofloxacin

in the inhaled aerosol” for LC STAR, LC+, and Sonix 2000 is “x = 0.11”; for T-

Updraft II is “x = 0.55”; and for Permaneb is “x = 11.1.” Ex. 1024 (Finlay) at 5-6.

B. Saiman

121. I have been informed by counsel and I understand that Saiman (Ex.

1025), published in September 1996, is prior art. Saiman is entitled “Antibiotic

Susceptibility of Multiply Resistant Pseudomonas aeruginosa Isolated from

Patients with Cystic Fibrosis, Including Candidates for Transplantation.”


65

122. Pseudomonas aeruginosa is a common bacterium that infects a large

majority of CF patients. Ex. 1025 (Saiman) at 4 (“… 81% of American patients

with CF are infected with P[seudomonas] aeruginosa by their mid-twenties …”).

Saiman “systematically studied the activity of 10 antimicrobial agents against

P[seudomonas] aeruginosa isolates from patients with CF who were not

responding to conventional antibiotic regimens, to establish the spectrum of

resistance in these clinical isolates.” Id. at 1. Relevant here, Saiman studied

ciprofloxacin at a concentration of “≤ 2 µg/mL.” Id. at 2.

123. Saiman received and tested 1,296 strains of Pseudomonas aeruginosa

taken from CF patients with Pseudomonas aeruginosa from 67 centers in 31 states.

Ex. 1025 (Saiman) at 1. Saiman found that with as little as 2 µg/mL of

ciprofloxacin, “21% of the 1,296 strains were resistant to” ciprofloxacin. Id. at 2,

3. In other words, a concentration of 2 µg/mL was effective in treating 79% of the

strains from patients with Pseudomonas aeruginosa.

C. Zhanel

124. I have been informed by counsel and I understand that Zhanel (Ex.

1026), published in 2002, is prior art.

125. Zhanel is a “critical review of fluoroquinolones” with a “focus on

respiratory tract infections. Ex. 1026 (Zhanel) at Title. Ciprofloxacin is a

fluoroquinolone, a type of quinolone. Id. at 5. Relevant here, Zhanel teaches that


66

the MIC50 (“minimum inhibitory concentration of 50% of isolates”) and MIC90

(“minimum inhibitory concentration of 90% of isolates”) values for ciprofloxacin

against Pseudomonas aeruginosa are 0.25 and 4 µg/mL, respectively. Id. at 12.

An abbreviated version of the table is reproduced below:

Source: Ex. 1026 (Zhanel) at 12.

D. Ciofu

126. I have been informed by counsel and I understand that Ciofu (Ex.

1027), published in June 2005, is prior art.

127. Ciofu is entitled “Occurrence of Hypermutable Pseudomonas

aeruginosa in Cystic Fibrosis Patients Is Associated with the Oxidative Stress

Caused by Chronic Lung Inflammation.” Ex. 1027 (Ciofu) at Title. Ciofu

discloses the following MIC50 and MIC90 values (including ciprofloxacin) of

hypermutable and nonhypermutable isolates of Pseudomonas aeruginosa:


67

Id. at 4, Table 1 (emphasis added).

128. In Dr. Leserman’s affidavit submitted during prosecution of the ’845

Patent, he relied on Ciofu to show that free ciprofloxacin concentrations greater

than MIC50 and MIC90 values of hypermutable and nonhypermutable isolates of

Pseudomonas aeruginosa is evidence of “free quinolone antibiotic agent in an

amount effective to provide immediate bactericidal activity against the pulmonary

infection,” as required in claim 1. Ex. 1003 (prosecution history of the ’845

Patent) at 304-311 (Dr. Leserman’s affidavit) at 310, ¶¶33-34.

E. Bakker

129. I have been informed by counsel and I understand that Bakker (Ex.

1029), published in August 2002, is prior art. Bakker is entitled “Ciprofloxacin in

Polyethylene Glycol-Coated Liposomes: Efficacy in Rat Models of Acute or

Chronic Pseudomonas aeruginosa Infection.” Bakker assessed combinations of

free and liposome-encapsulated ciprofloxacin in treating Pseudomonas aeruginosa.

130. In a previous study, Bakker examined liposome-encapsulated

ciprofloxacin that “was nontoxic and resulted in relatively high and sustained

ciprofloxacin concentration in blood and tissues” in relation to Klebsiella

pneumoniae. Ex. 1029 (Bakker) at Abstract. In this study, Bakker assessed the

same liposome-encapsulated ciprofloxacin in relation to Pseudomonas aeruginosa.

Id. at Abstract, 2 (“The present study was performed to investigate whether the


68

superior therapeutic potential of pegylated liposomal ciprofloxacin as observed in

the rat model of K. pneumonia pneumonia (5) could also be obtained in difficult-

to-treat infection caused by Pseudomonas aeruginosa with moderate susceptibility

to ciprofloxacin.”)

131. Bakker’s liposomes were made of DSPE-PEG 2000 (“PEG 2000

derivative of distearoylphosphatidylethanolamine”), HSPC (“hydrogenated

soybean phosphatidylcholine”) and cholesterol in a ratio of 5:50:45. Ex. 1029

(Bakker) at 2. HSPC is a type of phosphatidylcholine. Bakker’s liposomes had a

particle size of “107 ± 7.2 nm.” Id.

132. In Bakker, “antimicrobial treatment with CIP [free ciprofloxacin] and

PL Cipro [liposome-encapsulated ciprofloxacin] … in combination” was

“administered as bolus intravenous injections.” Ex. 1029 (Bakker) at 2, 3, Table 2

(“CIP + PL Cipro”).

133. Bakker discloses treatments comprising free and liposome-

encapsulated ciprofloxacin (“CIP + PL Cipro”):


69

Ex. 1029 (Bakker) at 3, Table 2. In the first treatment of free and liposome-

encapsulated ciprofloxacin, a 1:1 ratio of free and encapsulated drug was

administered on the first day; then for the next six days, only free ciprofloxacin

was administered. Id. Even if one accounts for the dosages of all seven days, the

weight ratio of free to liposome-encapsulated ciprofloxacin was 280:40 or 7:1. In

the third treatment of free and liposome-encapsulated ciprofloxacin, a 1:1 ratio of

free and encapsulated drug was administered on the first day; then for the next six

days, only liposome-encapsulated ciprofloxacin was administered. Id. Even if one

accounts for the dosages of all seven days, the weight ratio of free to liposome-

encapsulated ciprofloxacin was 40:280 or 1:7.

134. A POSITA understands that free and liposome-encapsulated

ciprofloxacin formulations are very effective therapeutic treatments against


70

Pseudomonas aeruginosa. Bakker teaches that administering both free and

liposome-encapsulated ciprofloxacin was more effective in treating acute

Pseudomonas aeruginosa pneumonia-septicemia than giving free ciprofloxacin or

liposome-encapsulated ciprofloxacin alone. Ex. 1029 (Bakker) at 3, Table 2. In

particular, administering a 7:1 total weight ratio of free to liposome-encapsulated

ciprofloxacin resulted in an 80% survival rate and a 1:7 total weight ratio resulted

in 100% survival rate. Id. In contrast, administering only free ciprofloxacin

resulted in, at best, a 38% survival rate, and administering only liposome-

encapsulated ciprofloxacin (at an equivalent daily dosing strength31) resulted in, at

best, a 73% survival rate. Id.

135. Notably, when comparing the liposome only treatment at 40

mg/kg/day with the third combination treatment (i.e., administering 40 mg/kg/day

of free ciprofloxacin on day 1 only and administering 40 mg/kg/day of liposome-

encapsulated ciprofloxacin for all 7 days), the initial burst of free ciprofloxacin

31 The first and third combination treatments (i.e., administering both free and

liposome-encapsulated ciprofloxacin) involved administering either 80 (day 1) or

40 (days 2-7) mg/kg of ciprofloxacin per day. The treatment involving 160

mg/kg/day of only liposome-encapsulated ciprofloxacin is not comparable to the

first and third combination treatments, because two to four times more

ciprofloxacin was administered every day.


71

(roughly 12.5% of the total amount of ciprofloxacin administered over 7 days)

resulted in a 100% survival rate compared to only 25% for the liposome only

treatment:

Ex. 1029 (Bakker) at 3, Table 2 (emphasis added). The immediate bactericidal

activity (on day 1) from the free ciprofloxacin led to a dramatic increase in survival

rate.

F. WO’341

136. I have been informed by counsel and I understand that WO’341 (Ex.

1030), with a priority date of October 24, 2006, is prior art to any claims that

cannot claim priority to the ’468 Provisional.

137. WO’341 teaches pharmaceutical compositions for inhalation to treat

respiratory tract infections, and methods of treating respiratory tract infections

using the pharmaceutical compositions. Ex. 1030 (WO’341) at [0001]; claims 1,


72

12. The drug can be administered by inhalation delivery devices such as

nebulizers. Id. at [0057].

138. The pharmaceutical compositions in WO’341 comprise free and

liposome-encapsulated drug (e.g., ciprofloxacin) as well as a pharmaceutically

acceptable excipient. Ex. 1030 (WO’341) at [0001], [0020], [0050]

(“ciprofloxacin is preferably used in the formulations of the instant invention”),

claims 1, 12. Those formulations can be in solutions or suspensions. Id. at [0060],

[0061], [0068]. WO’341 discloses formulations with free and liposome-

encapsulated drug (e.g., ciprofloxacin) at a weight ratio between 1:10 and 10:1. Id.

at [00112] (“combination of free and liposomal ciprofloxacin (0.36 mg/kg free and

0.6 mg/kg liposomal ciprofloxacin”); id. at [00113] (“38% free ciprofloxacin” and

62% liposomal ciprofloxacin). Examples 1-3 of WO’341 disclose liposomes

consisting of 70.6 mg/mL of hydrogenated soy phosphatidylcholine (HSPC) and

29.4 mg/mL of cholesterol. Id. at [0099], [00110], [00115], claim 6. The mean

diameters of the liposomes are in the range of “1 nm [or 0.001 µm] to 10 µm.” Id.

at [0053], claims 2, 5, 17. In one example, the mean diameter of the liposomes

was “75 to 120 nm [or 0.075 to 0.12 µm].” Id. at [0099].

139. WO’341 teaches that the combination of free and liposome-

encapsulated drug (e.g., ciprofloxacin) provide immediate and sustained release of

the drug:


73

a formulation comprising both a free and encapsulated

anti-infective provides an initially high therapeutic level

of the anti-infective in the lungs … while maintaining a

sustained release of antiinfective over time … . The

intent of the immediate-release anti-infective; e.g.,

ciprofloxacin, is thus to rapidly increase the antibiotic

concentration in the lung to therapeutic levels … . The

sustained-release anti-infective; e.g., ciprofloxacin,

serves to maintain a therapeutic level of antibiotic in the

lung thereby providing continued therapy over a longer

time frame, increasing efficacy, reducing the frequency

of administration, and reducing the potential for resistant

colonies to form.

Ex. 1030 (WO’341) at [0023], [0001], claims 1, 12.

140. The pharmaceutical compositions of WO’341 treat numerous

respiratory infections, such as bronchiectasis, tuberculosis (which is caused by

Mycobacterium tuberculosis) and Pseudomonas aeruginosa. Ex. 1030 (WO’341)

at [0034], [0097], [00113], claims 12, 13, 16.

G. Gay

141. I have been informed by counsel and I understand that Gay (Ex.

1028), published in July 1984, is prior art.

142. Gay is entitled “In Vitro Activities of Norfloxacin and Ciprofloxacin

Against Mycobacterium tuberculosis, M. avium complex, M. chelonei, M.

foruitum, and M. kansaii.” Ex. 1028 (Gay) at Title. Mycobacteria have the word


74

mycobacterium in their names and are usually abbreviated with “M.” Gay is a

“study []to determine the in vitro activities of norfloxacin and ciprofloxacin against

various species of Mycobacteria, including Mycobacterium tuberculosis, the

Mycobacterium avium complex, Mycobacterium chelonei, Mycobacterium

foruitum, and Mycobacterium kansaii.” Id. at 1. Gay teaches that ciprofloxacin

can be used to treat various mycobacteria; Table 1 in Gay discloses the MIC50 and

MIC90 values for various mycobacteria for ciprofloxacin:

Id. at 2.

XIV. OBVIOUSNESS ANALYSIS

143. I have been informed by counsel and I understand that an obviousness

analysis asks if the differences between the patented subject matter and the prior

art are such that the subject matter as a whole would have been obvious, at the time

the invention was made, to a POSITA to which said subject matter pertains.


75

144. I have been informed by counsel and I understand that obviousness is

a factual inquiry, where the following factors guide the analysis: (1) the scope and

content of the prior art; (2) the differences between the prior art and the claims at

issue; (3) the level of ordinary skill in the art; (4) and the so-called objective

secondary factors of nonobviousness (e.g., commercial success, long-felt unmet

need, unexpected results, copying).

145. I have been informed by counsel and I understand that obviousness

may be shown by a combination of prior art references. I understand that it is

important to consider whether there was a teaching, suggestion, or motivation to

combine elements found in the prior art, although an explicit teaching, suggestion,

or motivation to combine prior art references is not required. Rather, the following

factors may be considered in evaluating the existence of a motivation to combine:

(1) the inter-related teachings of multiple references; (2) the effects of demands

known to those of ordinary skill or present in the marketplace; and (3) the

background knowledge possessed by a POSITA.

146. I have been informed by counsel and I understand that, in order to

evaluate the obviousness of the ’845 Patent claims over a given prior art

combination, I should analyze whether the prior art references disclose every

limitation of the challenged claims either explicitly or inherently, as those

references are read by the POSITA at the time of the invention. Then I am to


76

determine whether that combination makes the claimed invention as a whole

obvious to the POSITA by a preponderance of the evidence, at the time of the

invention. I understand that the preponderance of the evidence standard is satisfied

as long as the proposition is more likely to be true than not true.

147. I have been informed by counsel and I understand that a patent

claiming a combination of elements from the prior art is obvious if the

improvement is no more than the predictable use of prior art elements according to

their established functions. When there is a design need or market pressure to

solve a problem and the prior art suggests a finite number of identified, predictable

solutions, a skilled artisan has good reason to pursue the known options within

their technical grasp. If this leads to the anticipated success, it is likely that the

product is not one of innovation but rather one of ordinary skill and common sense.

148. I have been informed by counsel and I understand that under an

obviousness analysis, all that is required is a reasonable expectation of success in

combining the prior art references. A guarantee or absolute certainty of success

based on the prior art is not required.

B. Claims 1-6, 8, 11-12, 14-16, 19, and 23 Are Invalid as Obvious over Finlay in View of Saiman or Zhanel or Ciofu

149. In developing a method of treating pulmonary infections using

liposome formulations, a POSITA would have been motivated to combine Finlay

(Ex. 1024) and Saiman (Ex. 1025) or Zhanel (Ex. 1026) or Ciofu (Ex. 1027).


77

Finlay teaches pharmaceutical formulations of free and liposome-encapsulated

ciprofloxacin that can be administered to the lungs of a patient in aerosolized form

via inhalation delivery devices, such as nebulizers. Finlay also teaches how much

free and liposome-encapsulated ciprofloxacin get delivered to the lungs. Saiman,

Zhanel, and Ciofu teach how much ciprofloxacin is necessary (with disclosed MIC

values for ciprofloxacin) to treat Pseudomonas aeruginosa (a common pulmonary

infection especially in CF patients).

150. Given their overlapping disclosures of ciprofloxacin for treating

pulmonary infections, a POSITA would have been motivated to combine Finlay

(Ex. 1024) and Saiman (Ex. 1025) or Zhanel (Ex. 1026) or Ciofu (Ex. 1027) to

determine whether the amount of ciprofloxacin delivered to the lungs in Finlay was

sufficient to provide bactericidal activity against a pulmonary infection caused by,

e.g., Pseudomonas aeruginosa.

1. Claim 1

a. “A method for treating or providing prophylaxis against a pulmonary infection in a patient in need thereof, comprising: administering to the lungs of the patient via an inhalation delivery device,”

151. A POSITA understands that the ciprofloxacin formulations disclosed

in Finlay treat pulmonary infections in patients. Finlay teaches:

The concept of encapsulating therapeutic agents inside

liposomal vesicles to enhance their effectiveness in the


78

treatment of respiratory disease by aerosol inhalation has

been studied by various authors.

…

Recent studies have shown that liposome-encapsulated

ciprofloxacin is significantly more effective than free

(unencapsulated) ciprofloxacin in the prevention and

treatment of intracellular bacterial infections of the

respiratory tract in mice.

Ex. 1024 (Finlay) at 1-2. The medicament in Finlay is administered to the lungs of

a patient via a nebulizer, an inhalation delivery device. Ex. 1001 (’845 Patent) at

12:40-42 (“The inhalation delivery device can be a nebulizer …”). A POSITA

understands that the purpose of a nebulizer is to deliver drug/medicament to the

lungs of a patient.

b. “a pharmaceutical formulation comprising a mixture of free quinolone antibiotic agent, a quinolone antibiotic agent encapsulated in a plurality of liposomes, and a pharmaceutical excipient,”

152. Finlay discloses “a pharmaceutical formulation comprising a mixture

of free quinolone antibiotic agent, a quinolone antibiotic agent encapsulated in a

plurality of liposomes, and a pharmaceutical excipient.” Ex. 1001 (’845 Patent) at

claim 1. Finlay discloses both pre- and post-nebulized formulations of free and

encapsulated quinolone (specifically ciprofloxacin). Ex. 1026 (Zhanel) at 5

(identifying ciprofloxacin as a fluoroquinolone, which is a type of quinolone).

Finlay’s pre-nebulized formulation contains “[l]iposome-encapsulated


79

ciprofloxacin” where “90 ±2%” of the ciprofloxacin is entrapped in liposomes. Ex.

1024 (Finlay) at 2. This means 10 ±2% of the ciprofloxacin is free. Finlay’s

formulation also contains a pharmaceutical excipient, “normal saline.” Id. (“A

concentration of 22.2 mg liposome-encapsulated-ciprofloxacin/ml in normal saline

was used for the nebulization in this study.”) (Emphasis added). The ’845 Patent

lists normal saline—also known as isotonic saline—as a “suitable” pharmaceutical

excipient. Ex. 1001 (’845 Patent) at 12:20.

153. Finlay also discloses five post-nebulized formulations of free and

encapsulated ciprofloxacin and normal saline. “2.5 ml of liposomal ciprofloxacin”

(which includes “90 ±2%” of liposome-encapsulated ciprofloxacin, 10 ±2% of free

ciprofloxacin, and normal saline) was nebulized in five different nebulizers. Ex.

1024 (Finlay) at 2-3. For the LC STAR, LC+, and Sonix 2000 nebulizers, the

“ratio, x, of free to encapsulated ciprofloxacin in the inhaled aerosol” is “0.11,”

which is 9.9% free drug and 90.1% encapsulated drug32. Id. at 5. For the

Permaneb nebulizer, the ratio of free to encapsulated ciprofloxacin in the inhaled

32 A ratio 0.11 is 11 parts free drug and 100 parts encapsulated drug. Thus, the %

weight of free drug is ��(�� )

��(�� ) x 100% = 9.9%. The % weight of

encapsulated drug is ��(�� )

��(�� ) x 100% = 90.1%.


80

aerosol is “11.1,” which is 91.7% free drug and 8.3% encapsulated drug33. Id. at 6.

For the T-Updraft II nebulizer, the ratio of free to encapsulated ciprofloxacin in the

inhaled aerosol is “0.55,” which is 35.5% free drug and 64.5% encapsulated drug34.

Ex. 1024 (Finlay) at 6. Accordingly, Finlay discloses the following post-nebulized

formulations:

TABLE I

Nebulizer % weight of free

ciprofloxacin

% weight of encapsulated

ciprofloxacin

LC STAR 9.9% 90.1%

LC+ 9.9% 90.1%

Sonix 2000 9.9% 90.1%

Permaneb 91.7% 8.3%

T-Updraft II 35.5% 64.5%



��(�� ) x 100% = 91.7%. The % weight of


��(�� ) x 100% = 8.3%.



��(�� ) x 100% = 35.5%. The % weight of


��(�� ) x 100% = 64.5%.


81

c. “wherein the formulation is a solution or a suspension,”

154. Finlay’s formulations are “a solution or a suspension,” as required by

claim 1 of the ’845 Patent. “A concentration of 22.2 mg liposome-encapsulated-

ciprofloxacin/ml in normal saline was used for the nebulization in this study.” Ex.

1024 (Finlay) at 2. “2.5 ml” of that solution was “nebulized in five units of each

nebulizer type.” Id. at 3.

d. “the ratio by weight of free quinolone antibiotic agent to the encapsulated quinolone antibiotic agent is between about 1:10 and about 10:1”

155. Finlay discloses pre- and post-nebulized formulations where “the ratio

by weight of free quinolone antibiotic agent to the encapsulated quinolone

antibiotic agent is between about 1:10 and about 10:1.” A ratio by weight of free

to encapsulated drug at 1:10, when converted to percentages, is 9.1% free drug

(�(�� )

��(�� ) x 100%) and 90.9% encapsulated drug

(��(�� )

��(�� ) x 100%). A ratio by weight of free to encapsulated

drug at 10:1, when converted to percentages, is 90.9% free drug and 9.1%

encapsulated drug. Accordingly, the range of the amount of free quinolone that

falls within the scope of this limitation is 9.1% to 90.9%; the corresponding range

of the amount of liposome-encapsulated drug that falls within the scope of this

limitation is 90.9% to 9.1%. As discussed above in ¶152, Finlay discloses pre-


82

nebulized “[l]iposome-encapsulated ciprofloxacin” formulations where “90 ±2%”

of the ciprofloxacin are entrapped in liposomes and 10 ±2% are free. Ex. 1024

(Finlay) at 2. The 10 ±2% free ciprofloxacin disclosed in Finlay meets this claim

limitation because it falls within 9.1% to 90.9%, and the “90 ±2%” of the

liposome-encapsulated ciprofloxacin disclosed in Finlay falls within the 90.9% to

9.1%. Id.

156. Furthermore, as shown in TABLE I above in ¶153, four of the five

post-nebulized formulations (i.e., LC STAR, LC+, Sonix 2000, and T-Updraft II)

in Finlay are mixtures of free and encapsulated ciprofloxacin that meet this claim

limitation. The formulations of LC STAR, LC+, and Sonix 2000 all contain 9.9%

free ciprofloxacin (which falls within 9.1% to 90.9%) and 90.1% liposome-

encapsulated ciprofloxacin (which falls within 90.9% to 9.1%). And the T-Updraft

II formulation contains 35.5% free ciprofloxacin (which falls within 9.1% to

90.9%) and 64.5% liposome-encapsulated ciprofloxacin (which falls within 90.9%

to 9.1%).

e. “and the lipid component of the plurality of liposomes consists of electrically neutral lipids,”

157. In Finlay, the “lipid component of the plurality of liposomes consists

of electrically neutral lipids.” Finlay’s liposomes consist of “phospahtidycholine

[sic]” and “cholesterol.” Ex. 1024 (Finlay) at 2. The ’845 Patent identifies

phosphatidycholine and cholesterol as “electrically neutral lipids.” Ex. 1001 (’845


83

Patent) at claim 6 (“The method of claim 1, wherein the electrically neutral lipids

consist of a phosphatidylcholine and a sterol.”), 7:1 (“The sterols can include,

cholesterol …”).

f. “wherein the pharmaceutical formulation is administered as an aerosolized pharmaceutical formulation,”

158. As discussed above, the pharmaceutical formulations of Finlay are

“administered as [] aerosolized pharmaceutical formulation[s]” via one of five

nebulizers. Ex. 1024 (Finlay) at 3 (“A volume fill of 2.5 ml of liposomal

ciprofloxacin taken directly from refrigeration (3.5 ± 0.5°C) was nebulized in five

units of each nebulizer type.”)

g. “and the aerosolized pharmaceutical formulation comprises free quinolone antibiotic agent in an amount effective to provide immediate bactericidal activity against the pulmonary infection and liposomal encapsulated quinolone antibiotic agent in an amount effective to provide sustained bactericidal activity against the pulmonary infection.”

159. A POSITA understands that the Finlay formulations were aerosolized

in nebulizers and contain “free quinolone antibiotic agent [i.e., ciprofloxacin] in an

amount effective to provide immediate bactericidal activity against the pulmonary

infection.” Ex. 1001 (’845 Patent) at claim 1. Pseudomonas aeruginosa, which is

identified in the ’845 Patent and was cited in Dr. Leserman’s affidavit, is a well-

known bacterium that causes chronic lung/pulmonary infections. Ex. 1001 (’845


84

Patent) at 8:56-58 (“The infective agent included in the scope of the present

invention may be … Pseudomonas aeruginosa …”); Ex. 1003 (prosecution history

of the ’845 Patent) at 304-311 (Dr. Leserman’s affidavit) at 310, ¶¶33-34. In fact,

two FDA approved aerosol formulations (TOBI® and CAYSTON® that I invented

and led the development of) are indicated for Pseudomonas aeruginosa. Ex. 1032

(TOBI®) at 2; Ex. 1033 (CAYSTON®) at 1. Having sufficient free ciprofloxacin

(a quinolone) to act against Pseudomonas aeruginosa provides immediate

bactericidal activity against a pulmonary infection.

160. As discussed above, during prosecution of the ’845 Patent, Patent

Owner’s expert Dr. Leserman submitted an affidavit where he attempted to show

that the prior art Yau-Young formulation did not have sufficient free ciprofloxacin

to provide immediate bactericidal activity. As discussed above, Dr. Leserman

applied a fundamentally flawed methodology. But for argument’s sake, I will

apply Dr. Leserman’s (and Patent Owner’s) methodology to Finlay with one

adjustment to show that Finlay meets this claim limitation under Patent Owner’s

logic. Rather than use Dr. Leserman’s assumption that 40% of the initially loaded

drug is delivered to the lungs, I will use the data reported in Finlay. Specifically,

in Finlay, with the T-Updraft II nebulizer, the amount of ciprofloxacin delivered to

the lungs (inhaled) comprises about 12.5% of the initially loaded ciprofloxacin that


85

is encapsulated in liposomes and about 6.5% (19% minus 12.5%) of the initially

loaded ciprofloxacin that is in free form. Ex. 1024 (Finlay) at 5, Fig. 2 (below).

I note that the T-Updraft II nebulizer (which delivers a total of 19% of the initially

loaded ciprofloxacin to the lungs) is far more inefficient than Dr. Leserman’s

assumption (which delivers a total of 40% of the initially loaded drug to the lungs).

In other words, the T-Updraft II nebulizer delivers less total ciprofloxacin

(liposome-encapsulated and free) to the lungs to provide bactericidal activity.

Even with that advantage given to the Patent Owner, as discussed in the next

paragraph, there is sufficient free ciprofloxacin in Finlay to provide immediate

bactericidal activity against Pseudomonas aeruginosa.

161. Starting with 150 mg (like Dr. Leserman) of Finlay’s liposomal-

encapsulated-ciprofloxacin, the T-Updraft II nebulizer delivers 9,750 µg of free

ciprofloxacin to the lungs of the patient (150 mg times 6.5% times 1,000 µg/mg).


86

Applying Dr. Leserman’s (incorrect) assumption that 4% of free quinolone is

“immediately available” for bactericidal activity, the free quinolone amount is 390

µg (i.e., 9,750 µg times 4%). Still following Dr. Leserman’s methodology and

applying the volume of the ASL (about 14 mL to about 20 mL), the concentration

of ciprofloxacin in the ASL is between 19.5 µg/mL (390 µg divided by 20 mL) and

27.9 µg/mL (390 µg divided by 14 mL). Applying Dr. Leserman’s methodology to

the LC STAR, LC+, and Sonix 2000 nebulizers results in the following

concentrations of free ciprofloxacin in the ASL that is available to provide

immediate bactericidal activity:

• LC STAR: 150 mg times 3.5% (i.e., 34.5% total minus 31%

encapsulated) times 1,000 µg/mg times 4% divided by either 20 mL

or 14 mL = 10.5 µg/mL to 15.0 µg/mL;

• LC+: 150 mg times 3% (i.e., 29.5% total minus 26.5% encapsulated)

times 1,000 µg/mg times 4% divided by either 20 mL or 14 mL = 9.0

µg/mL to 12.9 µg/mL;

• Sonix 2000: 150 mg times 2% (i.e., 20% total minus 18%

encapsulated) times 1,000 µg/mg times 4% divided by either 20 mL

or 14 mL = 6.0 µg/mL to 8.6 µg/mL.

The following table summarizes these calculations and shows the % inhaled

ciprofloxacin from Fig. 2 in Finlay:


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TABLE II

Nebulizer

Finlay’s Free Ciprofloxacin

Concentrations in ASL

(per Dr. Leserman’s methodology &

data reported in Finlay)

% Inhaled

Ciprofloxacin (as

% of initial dose)

T-Updraft II between 19.5 µg/mL and 27.9 µg/mL 19%

LC STAR between 10.5 µg/mL and 15.0 µg/mL 34.5%

LC+ between 9.0 µg/mL and 12.9 µg/mL 20%

Sonix 2000 between 6.0 µg/mL and 8.6 µg/mL 29.5%

Of note, all of the nebulizers in Finlay deliver less ciprofloxacin than Dr.

Leserman’s methodology (40%). In fact, even though the T-Updraft II delivers

less than half as much ciprofloxacin to the lung than Dr. Leserman’s methodology

(19% vs. 40%), the T-Updraft II nebulizer nonetheless delivers more free

ciprofloxacin (between 19.5 µg/mL and 27.9 µg/mL) than the lowest dose of free

drug in claim 1 of the ’845 Patent (between 10.8 µg/mL and 15.4 µg/mL).

162. Saiman teaches that as little as 2 µg/mL of ciprofloxacin treats nearly

80% of the strains from patients with Pseudomonas aeruginosa. Ex. 1025

(Saiman) at 2, 3. Saiman received and tested 1,296 strains of Pseudomonas

aeruginosa taken from CF patients with Pseudomonas aeruginosa from 67 centers

in 31 states. Id. at 1. Saiman found that with as little as 2 µg/mL of ciprofloxacin,

21% of the 1,296 strains were resistant to ciprofloxacin. Id. at 2, 3. In other


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words, a concentration of 2 µg/mL was effective in treating 79% of the strains

from patients with Pseudomonas aeruginosa. A POSITA would understand that a

dosage strength that treats nearly 80% of the strains from patients sufficiently

treats the infection and provides immediate bactericidal activity. As shown above

in TABLE II (¶161) , the free ciprofloxacin concentrations in the ASL for T-

Updraft II (between 19.5 µg/mL and 27.9 µg/mL), LC STAR (between 10.5

µg/mL to 15.0 µg/mL), LC+ (between 9.0 µg/mL to 12.9 µg/mL), and the Sonix

2000 (between 6.0 µg/mL to 8.6 µg/mL) all have free ciprofloxacin concentrations

much greater than 2 µg/mL; these nebulized formulations of Finlay will effectively

treat nearly 80% of the strains from patients with Pseudomonas aeruginosa.

Accordingly, based on the teachings of Saiman, at least the T-Updraft II, LC

STAR, LC+, and Sonix 2000 nebulizers of Finlay deliver “free quinolone

antibiotic agent [i.e., ciprofloxacin] in an amount effective to provide immediate

bactericidal activity against the pulmonary infection.”

163. Zhanel teaches that the MIC50 and MIC90 values for Pseudomonas

aeruginosa are 0.25 and 4 µg/mL, respectively. Ex. 1026 (Zhanel) at 12. As

shown above in TABLE II (¶161), the free ciprofloxacin concentrations in the ASL

for T-Updraft II (between 19.5 µg/mL and 27.9 µg/mL), LC STAR (between 10.5

µg/mL to 15.0 µg/mL), LC+ (between 9.0 µg/mL to 12.9 µg/mL), and the Sonix

2000 (between 6.0 µg/mL to 8.6 µg/mL) all have free ciprofloxacin concentrations


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that are much greater than 0.25 and 4 µg/mL. Accordingly, based on the teachings

of Zhanel, at least the T-Updraft II, LC STAR, LC+, and Sonix 2000 nebulizers of

Finlay deliver “free quinolone antibiotic agent [i.e., ciprofloxacin] in an amount

effective to provide immediate bactericidal activity against the pulmonary

infection.”

164. Ciofu (which is the reference Dr. Leserman relied on in his affidavit)

teaches MIC50 and MIC90 values for two groups of isolates of Pseudomonas

aeruginosa. For the hypermutable isolate, the MIC50 and MIC90 values are 12.5

and 25 µg/mL, respectively. Ex. 1027 (Ciofu) at 4, Table 1. For the

nonhypermutable isolates, the MIC50 and MIC90 values are 1.6 and 6.2 µg/mL,

respectively. Id. As shown above in TABLE II (¶161), the free ciprofloxacin

concentrations in the ASL for T-Updraft II (between 19.5 µg/mL and 27.9 µg/mL),

LC STAR (between 10.5 µg/mL to 15.0 µg/mL), and LC+ (between 9.0 µg/mL to

12.9 µg/mL) have free ciprofloxacin concentrations greater than the MIC50 values

for both hypermutable (12.5 µg/mL) and nonhypermutable (1.6 µg/mL) isolates of

Pseudomonas aeruginosa and the MIC90 value for nonhypermutable (6.2 µg/mL)

isolates of Pseudomonas aeruginosa. Those are the same reference points that

Patent Owner relied on during prosecution of the ’845 Patent to show immediate

bactericidal activity of its purported invention. Ex. 1003 (prosecution history of

the ’845 Patent) at 304-311 (Dr. Leserman’s affidavit) at 310, ¶¶33-34. For the T-


90

Updraft II in Finlay, the free ciprofloxacin concentration is greater than MIC90

value for hypermutable (25 µg/mL) isolates of Pseudomonas aeruginosa.

Accordingly, based on the teachings of Ciofu, at least the T-Updraft II, LC STAR,

and LC+ nebulizers of Finlay deliver “free quinolone antibiotic agent [i.e.,

ciprofloxacin] in an amount effective to provide immediate bactericidal activity

against the pulmonary infection.”

165. Finally, a POSITA understands that the Finlay formulations contain

“liposomal encapsulated quinolone antibiotic agent [i.e., ciprofloxacin] in an

amount effective to provide sustained bactericidal activity against the pulmonary

infection,” such as one caused by Pseudomonas aeruginosa. Ex. 1001 (’845

Patent) at 8:56-58 (“The infective agent included in the scope of the present

invention may be … Pseudomonas aeruginosa …”). It was well known in the art

that liposomal ciprofloxacin formulations provide “relatively high and sustained

ciprofloxacin concentrations in blood and tissues.” Ex. 1029 (Bakker) at Abstract.

As discussed above, in Finlay, with the T-Updraft II nebulizer, the total amount of

ciprofloxacin delivered is 19% of the initial dose, and 12.5 % of the initial dose of

ciprofloxacin is liposome-encapsulated ciprofloxacin. Starting with 150 mg (like

Dr. Leserman), 18.75 mg or 18,750 µg (150 mg times 12.5% times 1,000 µg/mg)

of liposome-encapsulated ciprofloxacin is delivered to the lungs. The

concentration of liposome-encapsulated ciprofloxacin in the ASL volume (either


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14 mL or 20 mL as determined by Dr. Leserman) is between 937.5 and 1,339.3

µg/mL. Doing the same calculations for LC STAR, LC+, and Sonix 2000 results

in concentrations of liposome-encapsulated ciprofloxacin in the ASL volume

between 2,325 and 3,321.4 µg/mL (150 mg times 31% times 1,000 µg/mg divided

by either 20 mL or 14 mL), between 1,350 and 1,928.6 µg/mL (150 mg times 18%

times 1,000 µg/mg divided by either 20 mL or 14 mL), and between 1,987.5 and

2,839.3 µg/mL (150 mg times 26.5% times 1,000 µg/mg divided by either 20 mL

or 14 mL), respectively.

166. As discussed above, ciprofloxacin concentrations as low as 2 µg/mL

effectively treated nearly 80% of Pseudomonas aeruginosa strains. Ex. 1025

(Saiman) at 2, 3. The MIC50 and MIC90 values for Pseudomonas aeruginosa are

0.25 and 4 µg/mL, respectively. Ex. 1026 (Zhanel) at 12. Nonhypermutable

isolates of Pseudomonas aeruginosa have MIC50 and MIC90 values of 1.6 and 6.2

µg/mL, respectively, and hypermutable isolates of Pseudomonas aeruginosa have

MIC50 and MIC90 values of 12.5 and 25 µg/mL, respectively. Ex. 1027 (Ciofu) at

4, Table 1. The amount of ciprofloxacin available in liposomes delivered by the T-

Updraft II, LC STAR, LC+, and Sonix 2000 nebulizers far exceed any of the

concentrations taught in Saiman, Zhanel, and Ciofu. A POSITA understands that

concentrations of liposome-encapsulated ciprofloxacin between 937.5 and 1,339.3

µg/mL (as well as between 2,325 and 3,321.4 µg/mL; between 1,350 and 1,928.6


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µg/mL; and between 1,987.5 and 2,839.3 µg/mL) are more than enough

ciprofloxacin to provide sustained bactericidal activity against Pseudomonas

aeruginosa.

2. Claims 2-4

a. “2. The method of claim 1, wherein the quinolone antibiotic agent is a fluoroquinolone”; “3. The method of claim 1, wherein the quinolone antibiotic agent is ciprofloxacin, enoxacin, gatifloxacin, grepafloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, sparfloxacin, trovafloxacin, oxolinic acid, gemifloxacin, or perfloxacin”; and “4. The method of claim 1, wherein the quinolone antibiotic agent is ciprofloxacin”

167. Finlay teaches the limitations of claims 2-4. Claims 2-4 further limit

the “quinolone antibiotic agent” in sole independent claim 1 to “a fluoroquinolone”

(claim 2) or “ciprofloxacin” (claims 3-4). In all of the Finlay formulations, the

antibiotic is ciprofloxacin. Ex. 1024 (Finlay) at 2. Ciprofloxacin is a

fluoroquinolone. Ex. 1026 (Zhanel) at 5 (identifying ciprofloxacin as a

fluoroquinolone).


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3. Claims 5-6, 8

a. “5. The method of claim 1, wherein the electrically neutral lipids consist of an electrically neutral phospholipid and a sterol”; “6. The method of claim 1, wherein the electrically neutral lipids consist of a phosphatidylcholine and a sterol”; and “8. The method of claim 6, wherein the sterol is cholesterol”

168. Finlay teaches the limitations of claims 5-6 and 8. Claims 5-6 further

limit the “electrically neutral lipids” in sole independent claim 1 to “consist of [an

electrically neutral phospholipid or a phosphatidycholine] and a sterol.” Claim 8

further limits the “sterol” in claim 6 to “cholesterol.” Phosphatidycholine is a type

of phospholipid. Ex. 1001 (’845 Patent) at 6:39-46. In all of the Finlay

formulations, the liposomes have “electrically neutral lipids” consisting of

“phospahtidycholine [sic]” and a sterol, “cholesterol.” Ex. 1024 (Finlay) at 2; Ex.

1001 (’845 Patent) at 7:1 (“The sterols can include, cholesterol …”).

4. Claims 11-12

a. “11. The method of claim 1, wherein the electrically neutral lipids consist of a phosphatidylcholine and a sterol, and the quinolone antibiotic agent is ciprofloxacin”; and “12. The method of claim 1, wherein the electrically neutral lipids consist of a phosphatidylcholine and cholesterol, and the quinolone antibiotic agent is ciprofloxacin”

169. Finlay teaches the limitations of claims 11-12. Claim 11 further limits

claim 1 by combining dependent claims 4 and 6: the “quinolone antibiotic agent”

in sole independent claim 1 is “ciprofloxacin,” and the “electrically neutral lipids”


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in sole independent claim 1 “consist of a phosphatidylcholine and a sterol.” Claim

12 further limits claim 1 by combining dependent claims 4 and 8: the “quinolone

antibiotic agent” in sole independent claim 1 is “ciprofloxacin,” and the

“electrically neutral lipids” in sole independent claim 1 “consist of a

phosphatidylcholine and cholesterol.”

170. In all of the Finlay formulations, the antibiotic is ciprofloxacin, and

the liposomes have “electrically neutral lipids” consisting of “phospahtidycholine

[sic]” and a sterol, “cholesterol.” Ex. 1024 (Finlay) at 2; Ex. 1001 (’845 Patent) at

7:1 (“The sterols can include, cholesterol …”).

5. Claims 14-15

a. “14. The method of claim 1, wherein the mean diameter of the plurality of liposomes is 0.01 micron to 3.0 microns”; and “15. The method of claim 14, wherein the mean diameter of the plurality of liposomes is 0.2 micron to 1.0 micron”

171. Finlay teaches the limitations of claims 14-15. Claims 14-15 further

limit the “plurality of liposomes” in sole independent claim 1 to a “mean diameter

of 0.01 micron[s] to 3.0 microns” and “0.2 micron[s] to 1.0 micron,” respectively.

In all of the Finlay formulations, the liposomes are extruded through a 0.2 µm35

pore size filter. Ex. 1024 (Finlay) at 2. Accordingly, the liposomes are about 0.2

35 I note that there is a typographical error in Finlay. Finlay’s pore size filter is 0.2

microns (µm), not millimeters. See footnote 30 supra.


95

microns (µm), and the mean diameter is about the size of the pore filter (0.2

microns (µm)); that size falls within “0.01 micron[s] and 3.0 microns,” as required

by claim 14 and meets the lower limit of “0.2 micron[s] to 1.0 micron,” as required

by claim 15. See, e.g., Ex. 1036 (Fenske) at 10 (“extruded, at relatively high

pressures (200-400 psi), through polycarbonate filters with a pore size ranging

from 30-400 nm, giving rise to narrow, monodisperse vesicle populations with

diameters close to the chosen pore size”) (emphasis added); Ex. 1035 (Cullis 1987)

at 11 (“extrusion … through … 100-nm pore size results in a relatively

homogeneous population of LUV[s] with a mean diameter of approximately 90

nm”), 14 (“extrusion … through 0.1 µm filters yields LUV systems (mean

diameter = 0.11 µm)”). In any event, a POSITA knows how to adjust the mean

diameter of liposomes: pick a different pore size filter to make LUVs (50 nm [or

0.05 microns] to 200 nm [or 0.20 microns]) or MLVs (“>400 nm” [or 0.4

microns]). Ex. 1036 (Fenske) at 10 (“extruded, at relatively high pressures (200-

400 psi), through polycarbonate filters with a pore size ranging from 30-400 nm,

giving rise to narrow, monodisperse vesicle populations with diameters close to the

chosen pore size”) (emphasis added); Ex. 1035 (Cullis 1987) at 7. It would be

obvious to a POSITA to make liposomes that fall within the mean diameter ranges

of claims 14 and 15.


96

6. Claim 16

a. “16. The method of claim 1, wherein the ratio by weight of free quinolone antibiotic agent to the encapsulated quinolone antibiotic agent is between about 1:2 and about 2:1”

172. Finlay teaches the limitation of claim 16, which further limits the

“ratio by weight of free quinolone antibiotic agent to the encapsulated quinolone

antibiotic agent” in sole independent claim 1 to “between about 1:2 and about 2:1.”

A ratio by weight of free to encapsulated drug at 1:2, when converted to

percentages, is 33.3% free drug (�(�� )

�(�� ) x 100%) and 66.7%

encapsulated drug (�(�� )

�(�� ) x 100%). A ratio by weight of

free to encapsulated drug at 2:1, when converted to percentages, is 66.7% free drug

and 33.3% encapsulated drug. Accordingly, the range of the amount of free

quinolone that falls within the scope of this limitation is 33.3% to 66.7%, and the

corresponding range of the amount of liposome-encapsulated drug that falls within

the scope of this limitation is 66.7% to 33.3%.

173. As shown in TABLE I above in ¶153, the post-nebulized formulation

of T-Updraft II in Finlay is a mixture of free and encapsulated ciprofloxacin that

meets this limitation. The T-Updraft II formulation contains 35.5% free

ciprofloxacin (which falls within 33.3% to 66.7%) and 64.5% liposome-

encapsulated ciprofloxacin (which falls within 66.7% to 33.3%).


97

7. Claim 19

a. “19. The method of claim 1, wherein the patient has bronchiectasis”

174. Finlay and Saiman or Zhanel or Ciofu teach the limitation of claim 19.

Claim 19 further limits sole independent claim 1 to a “patient ha[ving]

bronchiectasis.” Bronchiectasis is a disease associated with a permanent

enlargement of parts of the airways of the lung. The vast majority of CF patients

have bronchiectasis, and a large majority of CF patients are infected with

Pseudomonas aeruginosa. Ex. 1025 (Saiman) at 4 (“… 81% of American patients

with CF are infected with P[seudomonas] aeruginosa by their mid-twenties …”).

Thus, treating a patient who has bronchiectasis would also include treating

Pseudomonas aeruginosa. As discussed above in ¶¶158-166 with respect to claim

1, Finlay teaches a pharmaceutical formulation that, when administered via a

nebulizer, provides immediate and sustained bactericidal activity against

Pseudomonas aeruginosa. It is obvious to a POSITA that Finlay’s pharmaceutical

formulation, when administered via a nebulizer, could treat a patient with

bronchiectasis having Pseudomonas aeruginosa.

8. Claim 23

a. “23. The method of claim 1, wherein the inhalation delivery device is a nebulizer”

175. Finlay teaches the limitation of claim 23, which further limits the

“inhalation delivery device” in sole independent claim 1 to a “nebulizer.” To


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administer the liposomal ciprofloxacin, Finlay uses one of five nebulizers—LC

STAR, LC +, Sonix 2000, Permaneb, and T-Updraft II. Ex. 1024 (Finlay) at 2.

C. Claim 18 is Invalid as Obvious over Finlay in view of Gay

176. Claim 18 recites “[t]he method of claim 1, wherein the pulmonary

infection is a mycobacterial infection.” It would have been obvious for a POSITA

to administer the pharmaceutical formulations in Finlay to treat a mycobacterial

infection, based on the MIC values for various mycobacteria reported in Gay.

177. In developing a method for treating pulmonary infections caused by

mycobacteria with liposome formulations, a POSITA would have been motivated

to combine Finlay (Ex. 1024) and Gay (Ex. 1028). Finlay teaches pharmaceutical

formulations of free and liposome-encapsulated ciprofloxacin that can be

administered to the lungs of a patient in aerosolized form via inhalation delivery

devices, such as nebulizers. Finlay also teaches how much free and liposome-

encapsulated ciprofloxacin get delivered to the lungs. Gay teaches how much

ciprofloxacin is necessary (with disclosed MIC values for ciprofloxacin) to treat

pulmonary infections caused by mycobacteria.

178. Given their overlapping disclosures of ciprofloxacin for treating

pulmonary infections, a POSITA would have been motivated to combine Finlay

(Ex. 1024) and Gay (Ex. 1028) to determine whether the amount of ciprofloxacin


99

delivered to the lungs in Finlay was sufficient to provide bactericidal activity

against mycobacteria causing a pulmonary infection.

179. A mycobacterial infection is an infection caused by a mycobacterium.

Mycobacteria have the word mycobacterium in their names and are usually

abbreviated with “M.” Ex. 1028 (Gay) at 1 (“The purpose of this study was to

determine the in vitro activities of norfloxacin and ciprofloxacin against various

species of Mycobacteria, including Mycobacterium tuberculosis, the

Mycobacterium avium complex, Mycobacterium chelonei, Mycobacterium

foruitum, and Mycobacterium kansaii.”). Gay teaches that ciprofloxacin can be

used to treat various mycobacteria; Table 1 in Gay discloses the MIC50 and MIC90

values for various mycobacteria for ciprofloxacin:

Id. at 2. As shown above in TABLE II (¶161), the T-Updraft II (between 19.5 and

27.9 µg/mL), LC STAR (between 10.5 and 15.0 µg/mL), LC+ (between 9.0 and

12.9 µg/mL), and Sonix 2000 (between 6.0 and 8.6 µg/mL) in Finlay all delivered


100

concentrations of free ciprofloxacin greater than the MIC50 values for all five types

of mycobacteria disclosed in Gay. Id. (MIC50 values ranging from 0.25 to 2

µg/mL). Those four nebulizers do or could deliver concentrations of free

ciprofloxacin greater than the MIC90 values for four types of mycobacteria (i.e., M.

tuberculosis, M. chelonei, M. foruitum, and M. kansaii) disclosed in Gay. Id. And

the T-Updraft II nebulizer in Finlay delivered a concentration of ciprofloxacin

greater than the MIC90 value of the fifth mycobacterium, M. avium complex. Id.

Accordingly, based on the teachings of Gay, at least the T-Updraft II, LC STAR,

LC+, and Sonix 2000 nebulizers in Finlay of Finlay deliver “free quinolone

antibiotic agent [i.e., ciprofloxacin] in an amount effective to provide immediate

bactericidal activity against the pulmonary infection.” Further, the amount of

ciprofloxacin available in liposomes delivered by the T-Updraft II (between 937.5

and 1,339.3 µg/mL), LC STAR (between 2,325 and 3,321.4 µg/mL), LC+

(between 1,350 and 1,928.6 µg/mL), and Sonix 2000 (between 1,987.5 and 2,839.3

µg/mL) nebulizers in Finlay (as discussed above in ¶¶165-166) far exceed any of

the concentrations taught in Gay (0.25 to 16 µg/mL); a POSITA understands that

the liposome-encapsulated ciprofloxacin in Finlay is more than enough

ciprofloxacin to provide sustained bactericidal activity against mycobacteria that

cause a mycobacterial infection.


101

180. Based on a combination of Finlay in view of Gay, it would have been

obvious for a POSITA to arrive at the claimed method of dependent claim 18 of

the ’845 Patent.

D. Claims 7, 9-10, 13, 17, 22, and 24-26 Are Invalid as Obvious over Finlay in view of Bakker and Saiman or Zhanel or Ciofu

181. Claims 7, 9-10, 13, 17, 22, and 24-26 all depend from sole

independent claim 1, which is rendered obvious over Finlay (Ex. 1024) in view of

Saiman (Ex. 1025), or Zhanel (Ex. 1026), or Ciofu (Ex. 1027), as discussed above.

Claims 7, 9-10, 13, 17, 22, and 24-26 further require liposomes with “electrically

neutral lipids consist[ing] of hydrogenated soy phosphatidylcholine (HSPC) and a

sterol [or cholesterol].” It would have been obvious for a POSITA to replace the

phosphatidylcholine in Finlay’s liposome with HSPC, a specific

phosphatidycholine in Bakker’s liposome; both phosphatidycholines are known in

the art as lipid components in liposomes suitable for ciprofloxacin.

182. In developing a method of treating pulmonary infections using

liposome formulations, a POSITA would have been motivated to combine Finlay

(Ex. 1024), Bakker (Ex. 1029), and Saiman (Ex. 1025) or Zhanel (Ex. 1026) or

Ciofu (Ex. 1027). Finlay teaches pharmaceutical formulations of free and

liposome-encapsulated ciprofloxacin that can be administered to the lungs of a

patient in aerosolized form via inhalation delivery devices, such as nebulizers.

Finlay also teaches how much free and liposome-encapsulated ciprofloxacin get


102

delivered to the lungs. Finlay’s liposomes comprise phosphatidylcholine and

cholesterol at a ratio of 55:45. Ex. 1024 (Finlay) at 2. Like Finlay, Bakker teaches

pharmaceutical formulations administered as combinations of free and liposome-

encapsulated ciprofloxacin. Bakker’s liposomes, like Finlay’s, also comprise

phosphatidylcholine (specifically HSPC) and cholesterol at a ratio of 50:45. Ex.

1029 (Bakker) at 2.

183. As discussed above in ¶¶158-166, Finlay’s liposomes provide

treatment against Pseudomonas aeruginosa. Similar to Finlay, Bakker’s liposomes

also provide treatment against Pseudomonas aeruginosa. Ex. 1029 (Bakker) at 3,

Table 2:

184. Although Bakker teaches intravenous administration of free and

liposome-encapsulated ciprofloxacin, it is applicable to inhalation administration.


103

There are many ways to administer liposomes. Ex. 1034 (Betageri) at 21-24 (e.g.,

intravenous, intramuscular, lung administration, oral). To administer a liposomal

formulation via a nebulizer, a POSITA would load Bakker’s liposomal formulation

into a nebulizer for administration by inhalation.

185. Given the overlapping disclosures in Finlay and Bakker of

formulations with ciprofloxacin and liposomes comprising lipids made of

phosphatidylcholine and cholesterol, it would have been obvious to a POSITA to

replace the phosphatidylcholine in Finlay with HSPC, a specific

phosphatidylcholine in Bakker’s liposomes, in order to make a liposome with

lipids consisting of HSPC and cholesterol.

1. Claims 7 and 9

a. “7. The method of claim 6, wherein the phosphatidylcholine is hydrogenated soy phosphatidylcholine (HSPC)”; “9. The method of claim 7, wherein the sterol is cholesterol”

186. Claim 6 recites “[t]he method of claim 1, wherein the electrically

neutral lipids consist of a phosphatidylcholine and a sterol.” Ex. 1001 (’845

Patent) at claim 6. Claim 7 further limits the phosphatidylcholine to HSPC. Id. at

claim 7. Thus, to meet claim 7, the lipid component of the plurality of liposomes

consists of HSPC and a sterol. Id. at claims 1, 6, 7.


104

187. Claim 9 further limits claim 7 in that the sterol is cholesterol. Thus, to

meet claim 9, the lipid component of the plurality of liposomes consists of HSPC

and cholesterol. Ex. 1001 (’845 Patent) at claims 1, 6, 7, 9.

188. As discussed above in ¶¶181-185, it would have been obvious for a

POSITA to make a liposome whose lipid component consists of HSPC and

cholesterol, a sterol, as required by claims 7 and 9. Ex. 1001 (’845 Patent) at

claims 1, 6, 7, 9.

2. Claims 10, 13, and 24

a. “10. The method of claim 1, wherein the electrically neutral lipids consist of hydrogenated soy phosphatidylcholine (HSPC) and cholesterol and the quinolone antibiotic agent is a fluoroquinolone”; “13. The method of claim 1, wherein the electrically neutral lipids consist of hydrogenated soy phosphatidylcholine (HSPC) and cholesterol and the quinolone antibiotic agent is ciprofloxacin”; “24. The method of claim 7, wherein the quinolone antibiotic agent is ciprofloxacin”

189. Finlay and Bakker teach claims 10, 13, and 24. Claims 10 and 13

both require a “lipid component of the plurality of liposomes consists of [HSPC]

and cholesterol.” Ex. 1001 (’845 Patent) at claims 1, 10, 13. The difference

between claims 10 and 13 is that the quinolone antibiotic agent in claim 10 is

“fluoroquinolone” and in claim 13 is “ciprofloxacin.”

190. Claim 24 is akin to claim 13. Like claim 13, claim 24 requires

ciprofloxacin. Ex. 1001 (’845 Patent) at claims 13, 24. But claim 24 is broader


105

than claim 13 in that claim 24 requires a generic sterol whereas claim 13 requires a

specific sterol, cholesterol. Id. at claims 7, 13, 24.

191. As discussed above in ¶188, it would have been obvious for a


cholesterol, a sterol, as required by claims 10 and 13. And the antibiotic in all of

the Finlay and Bakker formulations is ciprofloxacin, a fluoroquinolone. Ex. 1026

(Zhanel) at 5 (identifying ciprofloxacin as a fluoroquinolone).

3. Claim 17

a. “17. The method of claim 13, wherein the ratio by weight of free ciprofloxacin to the encapsulated ciprofloxacin is between about 1:2 and about 2:1”

192. Finlay and Bakker teach claim 17. Claim 13 requires, in relevant part,

ciprofloxacin encapsulated liposomes with a “lipid component … consist[ing] of

HSPC and cholesterol.” Ex. 1001 (’845 Patent) at claims 1, 13. Claim 17 further

limits claim 13 by adding “the ratio by weight of free ciprofloxacin to the

encapsulated ciprofloxacin is between about 1:2 and about 2:1.”



cholesterol, as required by claim 13. Ex. 1001 (’845 Patent) at claims 1, 13. Also,

as discussed above in ¶¶172-173, Finlay teaches a pharmaceutical formulation with

a “ratio by weight of free ciprofloxacin to the encapsulated ciprofloxacin is


106

between about 1:2 and about 2:1”—the formulation of the T-Updraft II nebulizer.

Ex. 1024 (Finlay ) at 2-3, 5-6. In any event, a POSITA can easily adjust ratios of

free and liposome-encapsulated ciprofloxacin, e.g., by adding more free

ciprofloxacin, which leads to favorable results; as discussed above in ¶135

(discussing Bakker), adding free ciprofloxacin to a liposome only treatment

dramatically increased the survival rate.

4. Claims 22 and 26

a. “22. The method of claim 13, wherein the patient has bronchiectasis”; “26. The method of claim 22, wherein the pulmonary infection is a Pseudomonas aeruginosa infection”

194. Finlay and Bakker teach claims 22 and 26. Claim 13 requires, in

relevant part, ciprofloxacin encapsulated liposomes with a “lipid component …

consist[ing] of HSPC and cholesterol.” Ex. 1001 (’845 Patent) at claims 1, 13.

Claim 22 further limits claim 13 to a “patient ha[ving] bronchiectasis.” Claim 26

further limits claim 22 to a specific pulmonary infection, “Pseudomonas

aeruginosa.”




as discussed above in ¶174, Finlay and Saiman or Zhanel or Ciofu teach treating a

“patient ha[ving] bronchiectasis” and a “Pseudomonas aeruginosa infection.”


107

Bakker also teaches that its formulation treats a Pseudomonas aeruginosa

infection, which would also treat a patient with bronchiectasis. Ex. 1029 (Bakker)

at 3, Table 2; see ¶174 supra. Accordingly, it would have been obvious for a

POSITA to make a formulation of free ciprofloxacin and liposome-encapsulated

ciprofloxacin with liposomes having a lipid component consisting of HSPC and

cholesterol, and use that formulation to treat a “patient ha[ving] bronchiectasis,” as

required by claim 22, and a “Pseudomonas aeruginosa infection,” as required by

claim 26. Ex. 1001 (’845 Patent) at claims 22, 26.

5. Claim 25

a. “25. The method of claim 13, wherein the inhalation delivery device is a nebulizer”

196. Finlay and Bakker teach claim 25. Claim 13 requires, in relevant part,

ciprofloxacin encapsulated liposomes with a “lipid component … consist[ing] of

HSPC and cholesterol.” Ex. 1001 (’845 Patent) at claims 1, 13. Claim 25 further

limits claim 13 to a specific inhalation delivery device, “a nebulizer.”




as discussed above in ¶175, to administer the liposomal ciprofloxacin, Finlay uses

one of five nebulizers—LC STAR, LC +, Sonix 2000, Permaneb, and T-Updraft II.

Ex. 1024 (Finlay) at 2. A POSITA knows that any of those nebulizers in Finlay


108

can be used with the above formulation to administer ciprofloxacin to a patient’s

lungs.

E. Claims 20 and 21 Are Invalid as Obvious over Finlay in view of Bakker and Gay

198. Claims 20 and 21 both depend from dependent claim 13, which

requires liposomes with “electrically neutral lipids consist[ing] of hydrogenated

soy phosphatidylcholine (HSPC) and cholesterol.” Claims 20 and 21 further limit

claim 13 to treat specific pulmonary infections—“mycobacterial infection” and

“intracellular pulmonary infection,” respectively. The ’845 Patent explicitly

identifies Mycobacterium tuberculosis, a mycobacterial infection, as a type of

intracellular infection. Ex. 1001 at 4:55-58.


POSITA to replace the phosphatidycholine in Finlay’s liposome with HSPC, a

specific phosphatidycholine disclosed in Bakker, to make liposomes with

ciprofloxacin and a lipid component consisting of HSPC and cholesterol, as

required by claim 13. Ex. 1001 (’845 Patent) at claims 1, 13.

200. Gay teaches how much ciprofloxacin is necessary (with disclosed

MIC values for ciprofloxacin) to treat pulmonary infections caused by

mycobacteria, including “intracellular infections including Mycobacterium

tuberculosis.” Ex. 1028 (Gay) at 2; Ex. 1001 (’845 Patent ) at 4:55-58. As

discussed above in ¶¶176-180, Finlay and Gay teach treating a “mycobacterial


109

infection” caused by various mycobacteria or an “intracellular pulmonary

infection” caused by Mycobacterium tuberculosis.

201. It would have been obvious to a POSITA to make a formulation of

free and liposome-encapsulated ciprofloxacin with a lipid component consisting of

HSPC and cholesterol and use that formulation to treat a “mycobacterial infection”

caused by mycobacteria, as required by claim 20, or an “intracellular pulmonary

infection” caused by Mycobacterium tuberculosis, as required by claim 21. Ex.

1001 at claims 20, 21.

F. Claims 1-26 Are Invalid as Anticipated by WO’341

202. As discussed above, the claims of the ’845 Patent have an effective

filing date of the actual filing date January 4, 2016. I have been informed by

counsel that WO’341 was effectively filed on October 24, 2006. Accordingly, I

have been informed by counsel that WO’341 is prior art to the claims of the ’845

Patent.

1. Claim 1

a. “A method for treating or providing prophylaxis against a pulmonary infection in a patient in need thereof, comprising: administering to the lungs of the patient via an inhalation delivery device,”

203. WO’341 teaches a method of treating a pulmonary infection by

administering drug to the lungs of a patient via an inhalation delivery device. “The

present invention relates to a biphasic release formulation which provides


110

immediate and sustained release of a drug such as anti-infectives delivered by

inhalation for the treatment of cystic fibrosis” and pulmonary infections such as

“bronchiectasis, tuberculosis, pneumonia.” Ex. 1030 (WO’341) at [0001], [0097]

(emphases added). Original claim 12 of WO’341 describes a “method for treating

a patient, comprising[] aerosolizing a formulation … and inhaling the aerosol into

the patient’s lungs.” Id. at claim 12. That method can be used to treat “a

respiratory infection” or to “treat a disease” caused by, e.g., Pseudomonas

aeruginosa, which is a well-known bacterium that causes chronic lung/pulmonary

infections, especially in CF patients. Id. at claims 12, 13, 16; Ex. 1025 (Saiman) at

4 (around 1996, it was known that “81% of American patients with CF are infected

with P[seudomonas] aeruginosa by their mid-twenties.”). The medicament can be

administered by inhalation delivery devices such as nebulizers. Ex. 1030

(WO’341) at [0057].

b. “a pharmaceutical formulation comprising a mixture of free quinolone antibiotic agent, a quinolone antibiotic agent encapsulated in a plurality of liposomes, and a pharmaceutical excipient,”

204. WO’341 explicitly teaches pharmaceutical formulations comprising a

mixture of free and liposome-encapsulated quinolone (e.g., ciprofloxacin) and a

pharmaceutical excipient. “The free and liposome encapsulated drug are included

within a pharmaceutically acceptable excipient which is formulated for aerosolized

delivery.” Ex. 1030 (WO’341) at [0020]. WO’341 discloses:


111

a formulation comprising both a free and encapsulated

anti-infective provides an initially high therapeutic level

of the anti-infective in the lungs … while maintaining a

sustained release of antiinfective over time … . The

intent of the immediate-release anti-infective; e.g.,

ciprofloxacin, is thus to rapidly increase the antibiotic

concentration in the lung to therapeutic levels … . The

sustained-release anti-infective; e.g., ciprofloxacin,

serves to maintain a therapeutic level of antibiotic in the

lung thereby providing continued therapy over a longer

time frame, increasing efficacy, reducing the frequency

of administration, and reducing the potential for resistant

colonies to form.

Id. at [0023] (emphasis added).

205. Original claim 12 of WO’341 describes “a formulation comprising a

free first pharmaceutically active drug and a second pharmaceutically active drug

encapsulated in liposomes.” Id. at claim 12. Original claim 1 of WO’341 also

discloses:

An aerosolized composition of particles, comprising:

a free, unencapsulated first pharmaceutically active drug;

a pharmaceutically acceptable excipient; and

a liposome-encapsulated second pharmaceutically active

drug;

wherein the composition is formulated for aerosolized

delivery.


112

Id. at claim 1. Original claim 3 of WO’341 further limits the first and second

pharmaceutically active drug to ciprofloxacin. Id. at claims 1-3.

c. “wherein the formulation is a solution or a suspension,”

206. WO’341 explicitly teaches that the formulation can be a solution or a

suspension. “The liposomes may be provided as a suspension … .” Ex. 1030

(WO’341) at [0060]. “The liposomes are dissolved in solution … .” Id. “[T]he

ciprofloxacin-containing liposomes are provide in a solution formulation.” Id. at

[0061]. “A combination of immediate and sustained release formulations … may

be achieved via … suspensions … .” Id. at [0068].

d. “the ratio by weight of free quinolone antibiotic agent to the encapsulated quinolone antibiotic agent is between about 1:10 and about 10:1”

207. WO’341 explicitly describes formulations with weight ratios of free

and liposome-encapsulated ciprofloxacin between about 1:10 and about 10:1.

Table 1 of WO’341 discloses a formulation of a “combination of free and

liposomal ciprofloxacin” wherein 38% of the ciprofloxacin is free, meaning 62%

of the ciprofloxacin is encapsulated in liposomes; that translates to a 1:1.6 ratio,

which is within the range of “about 1:10 and about 10:1.” Ex. 1030 (WO’341) at

[00112] (“combination of free and liposomal ciprofloxacin (0.36 mg/kg free and

0.6 mg/kg liposomal ciprofloxacin)”), [00113]. Original claim 11 of WO’341 also

discloses an aerosolized composition “wherein the free anti-infective comprises


113

between about 1 and about 75% of the total free and liposome-encapsulated anti-

infective.” Id. at claim 11. A formulation with, e.g., 50% free and 50% liposome-

encapsulated drug is within the scope of original claim 11 of WO’341; that

translates to a 1:1 weight ratio and falls within the claimed range of “about 1:10

and about 10:1.”

e. “and the lipid component of the plurality of liposomes consists of electrically neutral lipids,”

208. WO’341 explicitly teaches liposomes with lipid components

consisting of electrically neutral lipids. Example 1 discloses:

liposomes consisting of hydrogenated soy phosphatidyl-

choline (HSPC) (70.6 mg/mL), a semi-synthetic fully

hydrogenated derivative of natural soy lecithin (SPC),

and cholesterol (29.4 mg/mL).

Ex. 1030 (WO’341) at [0099] (emphasis added); see also Examples 2-3, [00110],

[00115]. HSPC and cholesterol are electrically neutral lipids. Ex. 1001 (’845

Patent) at 6:44-45 (listing “hydrogenated egg and soya counterparts (e.g., HEPC,

HSPC)” as an electrically neutral lipid), claim 10 (“electrically neutral lipids

consist of hydrogenated soy phosphatidylcholine (HSPC) and cholesterol”).


114

f. “wherein the pharmaceutical formulation is administered as an aerosolized pharmaceutical formulation, and the aerosolized pharmaceutical formulation comprises free quinolone antibiotic agent in an amount effective to provide immediate bactericidal activity against the pulmonary infection and liposomal encapsulated quinolone antibiotic agent in an amount effective to provide sustained bactericidal activity against the pulmonary infection.”

209. WO’341 teaches administering aerosolized pharmaceutical

formulations wherein the free quinolone (e.g., ciprofloxacin) provides immediate

bactericidal activity and liposome-encapsulated quinolone (e.g., ciprofloxacin)

provides sustained bactericidal activity.

210. WO’341 describes that the “free and liposome encapsulated drug … is

formulated for aerosolized delivery.” Ex. 1030 (WO’341) at [0020]. “The present

invention relates to a biphasic release formulation which provides immediate and

sustained release of a drug such as anti-infectives delivered by inhalation for the

treatment of cystic fibrosis” and pulmonary infections such as “bronchiectasis,

tuberculosis, [and] pneumonia.” Ex. 1030 (WO’341) at [0001], [0097] (emphases

added). Original claim 12 of WO’341 describes a “method for treating a patient,

comprising[] aerosolizing a formulation … and inhaling the aerosol into the

patient’s lungs.” Id. at claim 12. That method can be used to treat “a respiratory

infection” or to “treat a disease” caused by, e.g., Pseudomonas aeruginosa, which

is a well-known bacterium that causes chronic lung/pulmonary infections,


115

especially in CF patients. Id. at claims 12, 13, 16; Ex. 1025 (Saiman) at 4 (around

1996, it was known that “81% of American patients with CF are infected with

P[seudomonas] aeruginosa by their mid-twenties.”).

211. WO’341 discloses that the formulation of free and liposome-

encapsulated ciprofloxacin “provides an initially high therapeutic level of the anti-

infective in the lungs … while maintaining a sustained release of anti-infective

over time.” Ex. 1030 (WO’341) at [0023]. “The intent of the immediate-release

anti-infective; e.g., ciprofloxacin, is thus to rapidly increase the antibiotic

concentration in the lung to therapeutic levels” and the “sustained-release anti-

infective; e.g., ciprofloxacin, serves to maintain a therapeutic level of antibiotic in

the lung, thereby providing continued therapy … .” Id.

2. Claims 2-4

a. “2. The method of claim 1, wherein the quinolone antibiotic agent is a fluoroquinolone”; “3. The method of claim 1, wherein the quinolone antibiotic agent is ciprofloxacin, enoxacin, gatifloxacin, grepafloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, sparfloxacin, trovafloxacin, oxolinic acid, gemifloxacin, or perfloxacin”; and “4. The method of claim 1, wherein the quinolone antibiotic agent is ciprofloxacin”

212. WO’341 teaches the limitations of claims 2-4. Claims 2-4 further

limit the “quinolone antibiotic agent” in sole independent claim 1 to “a

fluoroquinolone” (claim 2) or “ciprofloxacin” (claims 3-4). WO’341 teaches the


116

use of quinolones, “preferably ciprofloxacin.” Ex. 1030 (WO’341) at [0023],

[0050], [00113], claims 1-3, 12, 15. Ciprofloxacin is a fluoroquinolone. Ex. 1026

(Zhanel) at 5 (identifying ciprofloxacin as a fluoroquinolone).

3. Claims 5-9

a. “5. The method of claim 1, wherein the electrically neutral lipids consist of an electrically neutral phospholipid and a sterol”; “6. The method of claim 1, wherein the electrically neutral lipids consist of a phosphatidylcholine and a sterol”; “7. The method of claim 6, wherein the phosphatidylcholine is hydrogenated soy phosphatidylcholine (HSPC)”; “8. The method of claim 6, wherein the sterol is cholesterol”; “9. The method of claim 7, wherein the sterol is cholesterol”

213. WO’341 teaches the limitations of claims 5-9. Claims 5-9 further

limit the “electrically neutral lipids” in sole independent claim 1 to:

• “consist of an electrically neutral phospholipid and a sterol” (claim

5);

• “consist of a phosphatidylcholine and a sterol” (claim 6);

• “consist of hydrogenated soy phosphatidylcholine (HSPC) and a

sterol” (claim 7);

• “consist of a phosphatidylcholine and cholesterol” (claim 8);

• “consist of hydrogenated soy phosphatidylcholine (HSPC) and

cholesterol” (claim 9).

Ex. 1001 (’845 Patent) at claims 5-9.


117

214. WO’341 explicitly teaches a liposome with a lipid component

consisting of HSPC and cholesterol that satisfy claims 5-9. Ex. 1030 (WO’341) at

[0099], [00113]. HSPC (hydrogenated soy phosphatidylcholine) is an electrically

neutral phospholipids and a phosphatidylcholine. Ex. 1001(’845 Patent) at 6:44-

45 (listing electrically neutral lipids “hydrogenated egg and soya counterparts (e.g.,

HEPC, HSPC)”). Cholesterol is a sterol. Id. at 7:1. (“The sterols can include,

cholesterol …”).

4. Claims 10-13 and 24

a. “10. The method of claim 1, wherein the electrically neutral lipids consist of hydrogenated soy phosphatidylcholine (HSPC) and cholesterol and the quinolone antibiotic agent is a fluoroquinolone”; “11. The method of claim 1, wherein the electrically neutral lipids consist of a phosphatidylcholine and a sterol, and the quinolone antibiotic agent is ciprofloxacin”; “12. The method of claim 1, wherein the electrically neutral lipids consist of a phosphatidylcholine and cholesterol, and the quinolone antibiotic agent is ciprofloxacin”; “13. The method of claim 1, wherein the electrically neutral lipids consist of hydrogenated soy phosphatidylcholine (HSPC) and cholesterol and the quinolone antibiotic agent is ciprofloxacin”; “24. The method of claim 7, wherein the quinolone antibiotic agent is ciprofloxacin”

215. WO’341 teaches the limitations of claims 10-13 and 24, all of which

depend from claim 1. Claim 10 combines dependent claims 2 and 9: the

“quinolone antibiotic agent” in sole independent claim 1 is “fluoroquinolone” and


118

the “electrically neutral lipids” in sole independent claim 1 “consist of [HSPC] and

cholesterol.” Claim 11 combines dependent claims 4 and 6: the “quinolone

antibiotic agent” in sole independent claim 1 is “ciprofloxacin,” and the

“electrically neutral lipids” in sole independent claim 1 “consist of a

phosphatidylcholine and a sterol.” Claim 12 combines dependent claims 4 and 8:

the “quinolone antibiotic agent” in sole independent claim 1 is “ciprofloxacin,” and

the “electrically neutral lipids” in sole independent claim 1 “consist of a

phosphatidylcholine and cholesterol.” Claim 13 combines claims 4 and 9: the

“quinolone antibiotic agent” in sole independent claim 1 is “ciprofloxacin,” and the

“electrically neutral lipids” in sole independent claim 1 “consist of [HSPC] and

cholesterol.” Claim 24 combines claims 4 and 7: “quinolone antibiotic agent” in

sole independent claim 1 is “ciprofloxacin,” and the “electrically neutral lipids” in

sole independent claim 1 consist of a [HSPC] and a sterol.”

216. WO’341 explicitly teaches a liposome with a lipid component

consisting of HSPC and cholesterol encapsulating ciprofloxacin, a

fluoroquinolone, that satisfy claims 10-13 and 24. Ex. 1030 (WO’341) at [0099],

[00113]; Ex. 1026 (Zhanel) at 5 (identifying ciprofloxacin as a fluoroquinolone).

As discussed above in ¶214, HSPC is an electrically neutral phospholipid and a

phosphatidylcholine, and cholesterol is a sterol.


119

5. Claims 14-15

a. “14. The method of claim 1, wherein the mean diameter of the plurality of liposomes is 0.01 micron to 3.0 microns”; and “15. The method of claim 14, wherein the mean diameter of the plurality of liposomes is 0.2 micron to 1.0 micron”

217. WO’341 teaches the limitations of claims 14-15. Claims 14-15

further limit the “plurality of liposomes” in sole independent claim 1 to a “mean

diameter of 0.01 micron[s] to 3.0 microns” and “0.2 micron[s] to 1.0 micron,”

respectively. WO’341 discloses mean diameters of the liposomes in the range of

“1 nm [or 0.001 µm] to 10 µm,” which overlaps with the ranges in claims 14-15 of

the ’845 Patent. Ex. 1030 (WO’341) at [0053], claims 2, 5, 17. In one example,

the mean diameter of the liposomes was “75 to 120 nm [or 0.075 to 0.12 µm].” Id.

at [0099].

6. Claims 16 and 17

a. “16. The method of claim 1, wherein the ratio by weight of free quinolone antibiotic agent to the encapsulated quinolone antibiotic agent is between about 1:2 and about 2:1”; “17. The method of claim 13, wherein the ratio by weight of free ciprofloxacin to the encapsulated ciprofloxacin is between about 1:2 and about 2:1”

218. WO’341 teaches the limitation of claims 16-17. Claim 16 depends

from claim 1 and further limits the “ratio by weight of free quinolone antibiotic

agent to the encapsulated quinolone antibiotic agent” to “between about 1:2 and

about 2:1.” Ex. 1001 (’845 Patent) at claim 16. Claim 17 depends from claim 13


120

and like claim 16, further limits the “ratio by weight of free quinolone antibiotic

agent to the encapsulated quinolone antibiotic agent” to “between about 1:2 and

about 2:1.” Ex. 1001 (’845 Patent) at claim 17.

219. As discussed in ¶172, between 1:2 and 2:1, when converted to

percentages, is 33.3% to 66.7% free drug, and the corresponding range of

liposome-encapsulated drug is 66.7% to 33.3%. WO’341 explicitly teaches a

formulation with 38% free ciprofloxacin and 62% liposome-encapsulated

ciprofloxacin, which falls within the weight range of claims 16-17. Ex. 1030

(WO’341) at [00110]-[00113]. Those liposomes consist of HSPC and cholesterol,

as required by claim 17. Id. at [00110].

7. Claims 18 and 20-21

a. “18. The method of claim 1, wherein the pulmonary infection is a mycobacterial infection”; “20. The method of claim 13, wherein the pulmonary infection is a mycobacterial infection”; “21. The method of claim 13, wherein the pulmonary infection is an intracellular pulmonary infection”

220. WO’341 teaches the limitations of claims 18 and 20-21. Claim 18

depends from claim 1 and further limits the “pulmonary infection” to “a

mycobacterial infection.” Ex. 1001 (’845 Patent) at claim 18. Claims 20-21

depend from claim 13 and further limit the “pulmonary infection” to “a

mycobacterial infection” (like claim 18) and “an intracellular pulmonary

infection.” Id. at claims 20-21. The ’845 Patent explicitly identifies


121

Mycobacterium tuberculosis as a type of intracellular infection. Id. at 4:55-58.

WO’341 discloses that the anti-infectives in the formulations can be used to treat

“mycobacterial” infections. Ex. 1030 (WO’341) at [0034], claim 16 (listing

diseases to treat caused by a number of mycobacteria including Mycobacterium

tuberculosis).

8. Claims 19, 22, and 26

a. “19. The method of claim 1, wherein the patient has bronchiectasis”; “22. The method of claim 13, wherein the patient has bronchiectasis”; “26. The method of claim 22, wherein the pulmonary infection is a Pseudomonas aeruginosa infection”

221. WO’341 teaches the limitations of claims 19, 22, and 26. Claim 19

depends from claim 1 and further limits the patient to one who has bronchiectasis.

Ex. 1001 (’845 Patent) at claim 19. Claim 22 depends from claim 13 and like

claim 19, further limits the patient to one who has bronchiectasis. Id. at claim 22.

Claim 26 depends from claim 22 and further limits the “pulmonary infection” to “a

Pseudomonas aeruginosa infection.” Id. at claim 26. WO’341 explicitly discloses

that the method of treatment applies to patients with bronchiectasis and treats

Pseudomonas aeruginosa infections. Ex. 1030 (WO’341) at [0097], Examples 1-

2, claims 14, 16.


122

9. Claims 23 and 25

a. “23. The method of claim 1, wherein the inhalation delivery device is a nebulizer”; “25. The method of claim 13, wherein the inhalation delivery device is a nebulizer”

222. WO’341 teaches the limitation of claims 23 and 25. Claim 23

depends from claim 1 and further limits the “inhalation delivery device” to “a

nebulizer.” Ex. 1001 (’845 Patent) at claim 23. Claim 25 depends from claim 13

and like claim 23, further limits the “inhalation delivery device” to “a nebulizer.”

Id. at claim 25. WO’341 explicitly discloses that the drug can be administered by

inhalation delivery devices such as nebulizers. Ex. 1030 (WO’341) at [0057].

XV. SECONDARY CONSIDERATIONS

223. To the extent Patent Owner argues that secondary considerations

support a finding of non-obviousness with respect to the challenged claims, I

reserve the right to address any such arguments in Petitioner’s Reply. However, in

my opinion, secondary considerations do not overcome the strong evidence of

obviousness based on prior art.

224. There is no approved product embodying any of the claims; thus, with

respect to commercial success, there is no nexus to the claims of the ’845 Patent.


DECLARATION

I declare that all statements made herein on my own knowledge are true and

that all statements made on information and belief are believed to be true, and

further, that these statements were made with the knowledge that willful false

statsments and the like so made are punishable by fino or imprisonment, or both;

under Section 1001 of Title 18 of the United States Code.

Executed in Medina, WA on this 1st day of May 2017.

tgomery,


EXHIBIT A


CURRICULUM VITAE April 2017 Alan Bruce Montgomery, M.D. PERSONAL DATA Date of Birth: May 18, 1953 Place of Birth: Seattle, Washington Citizenship: USA Marital Status: Married, two children Current Home Address: 3455 Evergreen Point Road Medina, Washington 98039 Cell phone 206.390.2261 Email: [email protected] EDUCATION Undergraduate: University of Washington, Seattle, WA. 1975, B.S. in Chemistry Medical School: University of Washington, Seattle, WA. 1979, M.D. POSTGRADUATE TRAINING Internship and Residency in Internal Medicine: 6/79 to 6/82, University of Washington, Seattle, WA Pulmonary Research Fellow: 6/82 to 6/83, University of Washington, Seattle, WA Pulmonary and Critical Care Medicine Fellow: 7/83 to 7/85, University of California, San Francisco, CA HONORS Undergraduate: Magna cum Laude, Outstanding Chemistry Major (Merck Award), Phi Beta Kappa. Graduate: Alpha Omega Alpha honor medical society. Professional: Commissioner’s Special Citation, U. S. Food and Drug Administration, 1998 Patriotic Civilian Service Award, Secretary of the Army, U.S., 1997 Inventor of the Year, University of Washington, 2009 Distinguished Industrial Scientist, CF Foundation 2010 Breath of Life Award, CF Foundation 2007 and 2010 ISAM (International Society for Aerosols in Medicine) Career Achievement Award 2011 Timeless award (one of distinguished 150 living Arts and Sciences graduates of the University of Washington in celebration of the University’s 150th year) 2012 CAREER POSITIONS


6/85 to 6/87 Instructor of Medicine University of California, San Francisco and Cardiovascular Research Institute, Chest Service, San Francisco General Hospital. 6/87 to 11/88 Assistant Professor of Medicine in Residence University of California, San Francisco and Cardiovascular Research Institute, Chest Service, San Francisco General Hospital. 11/88 to 9/89 Assistant Professor of Medicine, Director of the Medical Intensive Care Unit, Pulmonary Disease Section, Department of Medicine, State University of New York, Stony Brook, NY 10/89 to 1/91 Associate Director of Clinical Research, Genentech, INC Created pulmonary and critical care department in Clinical Research. Recruited key personnel. Developed long-term clinical plan and initiated studies with rhDNase, a novel mucolytic. 1/91 to 11/93 Created department of new product development at Genentech. Identified or evaluated novel drug candidates from both intramural and extramural sources. Prepared extensive documentation with potential clinical and regulatory plans. Evaluated over 50 candidates of which five were selected for further research or for development. After selection, I designed with basic researchers the pivotal preclinical studies that determined whether the project proceeded. One project was rhu MAB E-25 (Xolair), a treatment for asthma and allergic diseases. Another is MAB CD11a (Raptiva), I am an inventor on the patent. 12/93 to 5/95 Vice President of Medical and Regulatory Affairs, PathoGenesis Corporation. Responsible for planning, budgeting and execution of clinical studies. Responsible for all FDA interactions. Initiated two clinical research programs. Conducted Phase II trial for TOBI, tobramycin solution for inhalation. 5/95 to 1/98 Senior Vice president for Research and Development, PathoGenesis Corporation. Had overall responsibility for Research and Development organization. Led 45 basic scientists in anti-infectious program, including genomics, molecular microbiology, microbiology, chemistry. Programs developed two preclinical drug candidates, ten patent applications and multiple peer-reviewed journal articles. Also, had overall responsibility for drug development, including pharmacology, toxicology, and human studies. Also led 70-member development team that developed, TOBI, tobramycin solution for inhalation for Pseudomonas infections in cystic fibrosis. FDA approval 12/22/97 after 11-0 FDA advisory board presentation. Received the Commissioner’s Special Citation, U. S. Food and Drug Administration in 1998 for this program. 1/98 to 10/00 Executive Vice President—overall responsibility for 150 person R&D operation inventing and developing novel antiinfectives. Scientific accomplishments, lead team that published Nature and Science articles in 2000, including the sequencing of the Pseudomonas Genone. Led the team that developed PA-824, a novel antibiotic for TB. Regulatory accomplishments: TOBI approved in Canada, United States, Australia, Europe, Argentina, and Israel. Conducted phase two clinical trials in Brazil for rifalazil, a rifampin class tuberculosis drug. Business accomplishments: During tenure of PathoGenesis, was one of three people responsible for raising 160 Million dollars in IPO and two secondary offerings. Developed three research and development collaborations with outside companies.


Also was instrumental in training and support of international sales force and affiliates. TOBI sales in 2000 exceeded 95 Million dollars. Was member of team that negotiated sale of the company to Chiron for 700 million dollars in September 2000. Investor relations: Presented at quarterly analyst calls, wrote or vetted all press releases, presented at over 100 analyst or investor meetings over the 7 years at PathoGenesis. 1/01 to 8/06 Chief Executive Officer Corus Pharma INC. Founder and CEO of development stage pharmaceutical company. Corus Pharma’s vision is to identify and rapidly develop pharmaceuticals that improve health and quality of life in the infectious and respiratory diseases areas. Raised 150 million dollars. Completed three programs through phase 2, one progressed to phase 3, aztreonam lysine for inhalation, a product for CF patients with pseudomonas lung infections. Sold Corus for enterprise value of 410 MM to Gilead Sciences in August 2006. 8/06 to 8/10 Senior Vice President, Respiratory Therapeutics. Transformed Corus Pharma into a division of Gilead Sciences. Successfully completed the aztreoanam lysine phase three trials and obtained regulatory approval in over 30 countries. Led an R and D team that moved 3 programs into clinical trials, one each in phase 1, phase 2 and phase 3. Built out the team from 80 to over 140 Seattle employees. Member of executive committee. 8/10 to 12/16 CEO Cardeas Pharma Biotechnology firm focused on treatment of multidrug resistant bacteria causing pneumonia in patients on mechanical ventilation. Raised 46 MM in Venture Capital 3/16 to now CEO Genoa Pharmaceuticals Biotechnology firm focused on treatment of idiopathic pulmonary fibrosis. Raised 60 MM in Venture Capital ACADEMIC POSITIONS (Noncareer) 10/89 to 11/93 Assistant Clinical Professor, University of California San Fransisco FEDERAL GOVERNMENT PUBLIC ADVISORY COMMITTEES 1/88 To 6/89 Member Pneumocystis carinii subcommittee of the opportuntistic infections committee of the AIDS evaluation and treatment evaluation units of the NIAID and protocol chairman of AETU protocol 040: A controlled trial comparing the efficacy of aerosolized pentamidine and parenteral/oral trimethoprim-sulfamethoxazole in the treatment of Pneumocystis pneumonia in AIDS. 2/89 to 2/91 Member of Public Health Task force on Anti-pneumocystis prophylaxis in patients infected with Human Immunodeficiency Virus


9/90 to 9/96 Member of the Army Science Board. Was cowriter on major technology application study. Chair of Soldier systems group. Had Dept. of Defense top secret security clearance LICENSES AND CERTIFICATIONS Medical License, Washington, 1979 Medical License, California, 1983 Medical License, New York, 1988 National Board of Medical Examiners, 1980 American Board of Internal Medicine, 1982 American Board of Internal Medicine, subspecialty certification in pulmonary, 1986 PROFESSIONAL SOCIETIES American Thoracic Society International Society for Aerosols in Medicine BOARD POSITIONS Alder Biotherapeutics 2010 to now Cytodyne 2013 to now Xencor 2015 to now M3Bio 2016 to now Vicis 2016 to now Trustee Washington State Life Sciences Discovery Fund 2005-2015 Charter trustee of up to 30MM year state sponsored research fund that has provided at least a 9 fold economic return to the state ZymoGenetics 2009 Sold to Bristol Myers Squibb for 880 MM Pacific Science Center 2000 to 2008 Second largest science center in the U.S. Washington State Biotechnology BioMedical Association 2000-2009 Chair 2004-2006 US PATENTS 9,533,00 Inhalable aztreonam for treatment and prevention of pulmonary infections 8,826,904 Formulations of aminoglycoside and fosfomycin combinations and methods and

systems for treatment of ventilator associated pneumonia (VAP) and ventilator associated tracheal (VAT) bronchitis

8,820,323 Methods to administer formulations of aminoglycoside and fosfomycin

combination for treatment of ventilator associated pneumonia (VAP) and ventilator associated tracheal (VAT) bronchitis


8,636,983 Aminoglycoside and fosfomycin combination for treatment of ventilator associated pneumonia (VAP) and ventilator associated tracheal (VAT) bronchitis

8,636,984 Aerosol formulation of aminoglycoside and fosfomycin combination for treatment

of ventilator associated pneumonia (VAP) and ventilator associated tracheal (VAT) bronchitis

8,603,439 Formulations of aminoglycoside and fosfomycin combinations and methods and

systems for treatment of ventilator associated pneumonia (VAP) and ventilator associated tracheal (VAT) bronchitis

8,003,081 Method for improvement of tolerance for therapeutically effective agents delivered by inhalation

7,998,463 Targeted delivery of lidocaine and other local anesthetics and a method for treatment of cough, asthma and tussive attacks

7,973,029 Inhaled aztreonam lysine for the treatment of deficits in health-related quality-of-life in lung diseases

7,452,524 Method for improvement of tolerance for therapeutically effective agents delivered by inhalation

7,452,523 Targeted delivery of lidocaine and other local anesthetics and a method for treatment of cough and tussive attacks

7,427,633 Inhalable aztreonam lysinate formulation for treatment and prevention of pulmonary bacterial infections

7,214,364 Inhalable aztreonam lysinate formulation for treatment and prevention of pulmonary bacterial infections

7,208,141 Inhalable aztreonam aerosol for treatment and prevention of pulmonary bacterial infections

6,660,249 Inhalable dry powder aztreonam for treatment and prevention of pulmonary bacterial infections

6,566,354 Method for treatment of bacterial infections with once or twice-weekly administered rifalazil

6,387,886 Method for the treatment of severe chronic bronchitis (bronchietasis) with an aerosolized antibiotic

6,316,433 Method for treatment of bacterial infections with once or twice-weekly administered rifalazil

6,083,922 Method and a tobramycin aerosol formulation for treatment prevention and containment of tuberculosis

5,767,068 Pure biologically active colistin, its components and a colistin formulation for treatment of pulmonary infections

5,622,700 Method for treating a LFA-1-mediated disorder

5,508,269 Aminoglycoside formulation for aerosolization


5,366,726 Suppression of Pneumocystis carinii using aerosolized pentamidine treatment

5,364,615 Prophylaxis of Pneumocystis carinii with aerosolized pentamidine

3 patent applications pending


PUBLICATIONS: ARTICLES

Moore TA, Montgomery AB, Kwiram AL. Triplet electronic structure and photoreactivity of 8-methoxypsoralen. Photochemistry and Photobiology 24:83-86, 1976.

Stillman PL, May JR, Meyer DM, Rutala PJ, Veach TL, Montgomery AB. A collaborative effort to study methods of teaching physical examination skills. J Medical Education 56:301-307, 1981.

Montgomery AB, Griffin T, Parker RG, Gerdes AJ. Optic nerve glioma: the role of radiation therapy. Cancer 40:2079-2080, 1977.

Montgomery AB, Stager MA, Carrico CJ, Hudson LD. Causes of mortality in patients with the adult respiratory distress syndrome. Am Rev Respir Dis132:485-489, 1985.

Montgomery AB, Luce JL. Infection monitoring in the intensive care unit. Respiratory Care 30:489-499, 1985.

Montgomery AB, Stager MA, Schoene RB. Marked suppression of ventilation while awake following massive ingestion of atenolol. Chest 88:920-921, 1985.

Montgomery AB, Paajanen H, Brasch RC, Murray JF. Aerosolized gadolinium-DTPA enhances the magnetic resonance signal of extravascular lung water. Investigative Radiology 22:377-381, 1987.

Montgomery AB, Holle RHO, Neagley SR, Pierson DJ, Schoene RB. Prediction of successful ventilator weaning using airway occlusion pressure and hypercapnic challenge. Chest 91:496-499, 1987.

Huchon GJ, Montgomery AB, Lipavsky A, Hoeffel JM, Murray JF. Respiratory clearance of aerosolized radioactive solutes of varying molecular weight. Journal of Nuclear Medicine 28:894-902, 1987.

Debs RJ, Blumenfeld W, Brunette EN, Straubinger RM, Montgomery AB, Lin E, Agabian N, Papahadjopoulos D. Successful treatment with aerosolized pentamidine of Pneumocystis carinii pneumonia in rats. Antimicrob Agents and Chemo 31:37-41,1987.

Debs RJ, Straubinger RM, Brunette EN, Lin JM, Lin EJ, Montgomery AB, Friend DS, Papahadajopoulos DP. Selective enhancement of pentamidine uptake in the lung by aerosolization and delivery in liposomes. Am Rev Respir Dis 135:731-737, 1987.

Montgomery AB, Debs RJ, Luce JM, Corkery K, Turner J, Brunette EN, Lin ET, Hopewell PC. Selective delivery of pentamidine to the lung by aerosol. Am Rev Respir Dis 1988, 137:477-488.


Montgomery AB, Debs RJ, Luce JM, Corkery K, Turner J, Brunette EN, Lin ET, Hopewell PC. Aerosolised pentamidine as sole therapy for Pneumocystis carinii pneumonia in patients with acquired immunodeficiency syndrome. Lancet 2:480-483, 1987.

Debs RJ, Montgomery AB, Brunette EN, DeBruin M, Shanley JD. Treatment of Murine Cytomegalovirus Lung Infection by Aerosol Administration of Antiviral Agents. J Inf Dis 157:327-331,1988.

Huchon GJ, Montgomery AB, Lipavsky A, Hoeffel JM, Murray JF. Pulmonary clearance of three aerosolized solutes in oleic acid-induced lung injury. J Appl Physio 64:1171-1178,1988 .

Luce JM, Montgomery AB, Marks JD, Turner J, Metz CA, Murray JF. Ineffectiveness of high dose Methylprednisolone in preventing parenchymal lung injury and improving mortality in septic shock. Am Rev Respir Dis 138:62-68, 1988

Debs RJ, Fuchs HJ, Philip R, Montgomery AB, Brunette EN, Liggitt D, Patton JS, Shellito J. Lung-specific delivery of cytokines induces sustained pulmonary and systemic immunomodulation in rats. J of Immunology 1988; 140:3482-3488.

Corkery KJ, Luce JM, Montgomery AB. Aerosol Pentamidine for treatment and prophylaxis of Pneumocystis carinii pneumonia: an update. Respiratory Care 1988; 33:676-685.

Montgomery AB, Debs RJ, Luce JM, Corkery K J, Turner J, Hopewell PC. Aerosolised pentamidine as second line therapy in patients with acquired immunodeficiency syndrome and Pneumocystis carinii pneumonia . Chest 95:747-750, 1989.

Montgomery AB. Pathophysiology, Therapy and Prevention of Pneumocystis carinii Pneumonia

in Patients with the Acquired Immunodeficiency Syndrome. Seminars in Respiratory Medicine, 4:102-110,1989

Montgomery AB, Mills J, Luce JM. Incidence of acute mountain sickness at intermediate altitude. JAMA, 261:732-734,1989.

Montgomery AB, Luce JM, Michaels P, Mills J. Effects of Dexamethasone on the Incidence of Acute Mountain Sickness at two Intermediate Altitudes. JAMA 261:734-736, 1989. Montgomery AB, Luce JM, Murray JF. Retrosternal pain is the first indication of oxygen toxicity.

Am Rev Respir Dis 139:1548-1550, 1989 Montgomery AB. Current status of aerosolized Pentamidine for treatment and prevention of

Pneumocystis carinii pneumonia . J Aerosol Med 2:233-238, 1989. Montgomery AB. Prophylaxis of Pneumocystis carinii pneumonia in patients infected with HIV

Type 1. Seminars in Respiratory Infections 4:311-317, 1989.


Montgomery AB, Feigal DW. Aerosolized Pentamidine-the North American experience.Suppl to JAMA SEA 6:61-66.

Montgomery AB. How the recent changes in expedited drug approval procedures affect the work of

a clinical investigator. Food Drug Cosmetic Law Journal 45:339-346, 1990 Rubin DB, Wiener-Kronish JP, Murray JF, Green DR, Turner JM, Montgomery AB, Marks JB,

Matthay. Elevated von Willebrand antigen is an early plasma predictor of acute lung injury in nonpulmonary sepsis syndrome. J Clin Invest 86:474-480, 1990

Marks JD, Marks CB, Luce JM, Montgomery AB, Turner J, Metz CA, Murray JF. Plasma tumor

necrosis factor in patients with Septic Shock. Am Rev Respir Dis 141:94-97, 1990. Debs R, Brunette E, Fuchs H, Lin E, Shah M, Hargis A, Montgomery AB. Biodistribution, tissue

reaction , and lung retention of pentamidine aerosolized as three different salts. Am Rev Respir Dis 142:1164-1167, 1990.

Montgomery AB, Corkery KJ, Brunette ER, Leoung GS, Waskin H, Debs RJ. Occupational

exposure to aerosolized pentamidine. Chest 98:386-388, 1990. Leoung GS, Feigal DW Jr, Montgomery AB, et al. Aerosolized pentamidine for prophylaxis

against Pneumocystis carinii pneumonia. N Engl J Med 1990; 323:769-75. Aitken ML, Burke W, McDonald G, Shak S, Montgomery AB, Smith A. Recombinant Human

DNase Inhalation in Normal Subjects and Patients with Cystic Fibrosis. JAMA 1992; 267:1947-1951.

Montgomery AB, Feigal Jr. DW, Sattler F et al. Pentamidine aerosol versus trimethoprim- sulfamethoxazole for Pneumocystis carinii in acquired immunodeticiency syndrome. Am. J. Respir. Crit. Care Med. 1995; 1068- 74. Ramsey, BW, Pepe, MS, Quan, JM, Otto, KL, Montgomery, AB, et al. Intermittent Administration of Inhaled Tobramycin in Patients with Cystic Fibrosis, NEJM 1999; 340:23-30. Burns, JL, Van Dalfsen, JM, Shawar, RM, Otto, KL, Garber, RL, Quan, JM, Montgomery, AB, et al. Effect of Chronic Intermittent Administration of Inhaled Tobramycin on Respiratory Microbial Flora in Patients with Cystic Fibrosis, JID 1999;179 (May). Standaert, TA, VanDevanter D, Ramsey BW, Vasiljev-K M, Nardella P, Gmur D, Bredl C,

Murphy A, and Montgomery AB. The choice of compressor effects aerosol parameters and delivery of Tobramycin from a single model nebulizer, Journal of Aerosol Med, 2000:13;147-153. Rosenfeld, M, Emerson J, Williams-Warren, J, Pepe, M, Smith A, Montgomery AB, Ramsey B. Defining a pulmonary exacerbation in cystic fibrosis. J Pediatr 2001; 139:359-65.


Margaret Rosenfeld, MD, MPH, Ron Gibson, MD, PhD, Sharon McNamara, MN, Julia

Emerson, MD, MPH, Karen S. McCoy, MD, Richard Shell, MD, Drucy Borowitz, MD, Michael W. Konstan, MD, George Retsch-Bogart, MD, Robert W. Wilmott, MD, Jane L. Burns, MD, Paolo Vicini, A. Bruce Montgomery, Bonnie Ramsey, MD. Serum and lower respiratory tract drug concentrations after tobramycin inhalation in young children with cystic fibrosis. J Pediatr 2001; 139:572-577.

Retsch-Bogart, G. Z., Burns, J. L., Otto, K. L., Liou, T. G., McCoy, K., Oermann, C. and Gibson, R. L. (2008), A phase 2 study of aztreonam lysine for inhalation to treat patients with cystic fibrosis and Pseudomonas aeruginosa infection. Pediatric Pulmonology, 43: 47–58.

Karen S. McCoy, Alexandra L. Quittner, Christopher M. Oermann, Ronald L. Gibson, George Z. Retsch-Bogart and A. Bruce Montgomery. Inhaled Aztreonam Lysine for Chronic Airway Pseudomonas aeruginosa in Cystic Fibrosis Am. J. Respir. Crit. Care Med. 2008; 178(9):921-8.

George Z. Retsch-Bogart, Alexandra L. Quittner, Ronald L. Gibson, Christopher M. Oermann, Karen S. McCoy, A. Bruce Montgomery, and Peter J. Cooper Efficacy and Safety of Inhaled Aztreonam Lysine for Airway Pseudomonas in Cystic Fibrosis Chest May 2009 135:1223-1232;

Oermann CM, Retsch-Bogart GZ, Quittner AL, et al. An 18-month study, AIR-CF3, of the safety and improvement in pulmonary function and respiratory symptoms with repeated courses of aztreonam for inhalation solution in patients with cystic fibrosis and airway Pseudomonas aeruginosa. Pediatr Pulmonol 2010; 45:1121-1134.

Tammy Abuan, Melissa Yeager, A. Bruce Montgomery. Inhaled Lidocaine for the Treatment of Asthma: Lack of Efficacy in Two Double-Blind, Randomized,Placebo-Controlled Clinical Studies. Journal of Aerosol Medicine and Pulmonary Drug Delivery. December 2010, 23(6): 381-388 C.E. Wainwright, A.L. Quittner, D.E. Geller, C. Nakamura, J.L. Wooldridge, R.L. Gibson,

S. Lewis, A.B. Montgomery Aztreonam for inhalation solution (AZLI) in patients with cystic fibrosis, mild lung impairment, and P. aeruginosa Journal of Cystic Fibrosis 2011(10):234-242.

Oermann CM, McCoy KS, Retsch-Bogart GZ, Gibson RL, McKevitt M, Montgomery AB .Pseudomonas aeruginosa antibiotic susceptibility during long-term use of aztreonam

for inhalation solution (AZLI). J Antimicrob Chemother. 2011 Oct;66(10):2398-404.

O'Sullivan AK, Sullivan J, Higuchi K, Montgomery AB. Health care utilization & costs for cystic fibrosis patients with pulmonary infections. Manag Care. 2011 Feb;20(2):37-44.


Bruce C. Trapnell, Susanna A. McColley, Dana G. Kissner, Mark W. Rolfe, Jonathan M. Rosen,

Matthew McKevitt, Lisa Moorehead, A. Bruce Montgomery, and David E. Geller for the Phase 2 FTI Study Group Fosfomycin/Tobramycin for Inhalation in Patients with Cystic Fibrosis with Pseudomonas Airway Infection Am. J. Respir. Crit. Care Med. 2012;185 171-178

Alan Bruce Montgomery, T. Abuan, and Melissa A. Yeager. Regulatory Aspects of Phase 3 Endpoints for New Inhaled Antibiotics for Cystic Fibrosis Patients with Chronic Pseudomonas aeruginosa Infections Journal of Aerosol Medicine and Pulmonary Drug Delivery. August 2012, 25:198-203.

Baroukh M. Assael, Tacjana Pressler, Diana Bilton, Michael Fayon, Rainald Fischer, Raphael Chiron, Mario LaRosa, Christiane Knoop, Noel McElvaney, Sandra A. Lewis, Mark Bresnik, A. Bruce Montgomery, Christopher M. Oermann, For the AZLI Active Comparator Study Group. Inhaled aztreonam lysine vs. inhaled tobramycin in cystic fibrosis: A comparative efficacy trial Journal of Cystic Fibrosis 2013 12:130-140

Ganesh Raghu, Juergen Behr, Kevin Brown, Jim Egan, Steven Kawut, Kevin Flaherty, Fernando Martinez, Steven Nathan, Athol Wells, Harold Collard, Ulrich Costabel, Luca Richeldi, Joao de Andrade, Nasreen Khalil, Lake Morrison, David Lederer, Lixin Shao, Patty Pedersen, Bruce Montgomery, Thomas O'Riordan, Jason Chien, Xiaoming Li. ARTEMIS-IPF: Treatment of Idiopathic Pulmonary Fibrosis with Ambrisentan, a Selective Antagonist of the Endothelin A Receptor: A Randomized Trial. Annals of Internal Medicine 2013 158:1-32.

Kollef MH; Hamilton CW, Montgomery AB. Aerosolized antibiotics: do they add to the treatment of pneumonia? Current Opinion in Infectious Diseases: 2013 26: 538–544

Montgomery AB, Rhomberg R, AbuanT, Walters KA,.Flamm RK. Potentiation Effects of Amikacin and Fosfomycin against Selected Amikacin-Nonsusceptible Gram-Negative Respiratory Tract Pathogens. Antimicrob. Agents Chemother. July 2014 58: 3714-3719.

Montgomery AB, Rhomberg R, AbuanT, Walters KA,.Flamm RK. Amikacin/fosfomycin (5:2 ratio): characterization of mutation rates in microbial strains causing ventilator-associated pneumonia and interactions with commonly used antibiotics. Antimicrob. Agents Chemother 2014 58: 3720-3725.

Montgomery AB, Vallance S, Abuan T, Tservistas M, Davies A. A Randomized Double-Blind Placebo-Controlled Dose-Escalation Phase 1 Study of Aerosolized Amikacin and Fosfomycin Delivered via the PARI Investigational eFlow_ Inline Nebulizer System in Mechanically Ventilated Patients. Journal of Aerosol Medicine and Pulmonary Drug Delivery 2014 27:441-8


O'Riordan Thomas G., Donn Karl H., Hodsman Peter, Ansede John H., Newcomb Terry, Lewis Sandra A., Flitter William D., White Vicki Shigekane, Johnson M. Ross, Montgomery A. Bruce, Warnock David G., and Boucher Richard C. Acute Hyperkalemia Associated with Inhalation of a Potent ENaC Antagonist: Phase 1 Trial of GS-9411 Journal of Aerosol Medicine and Pulmonary Drug Delivery. June 2014, 27(3): 200-208.

Raghu G, Lynch D, Godwin JD, Webb R,Colby TV, Leslie KO, Behr J, Brown, KK, Egan JJ, Flaherty KR, Martinez FJ, MD, Wells AU, Lixin Shao L, Zhou H, Pedersen PS, Sood R, MD, Montgomery AB, O'Riordan TG, Diagnosis of idiopathic pulmonary fibrosis with high-resolution CT in patients with little or no radiological evidence of honeycombing: secondary analysis of a randomised, controlled trial The Lancet Respiratory Medicine – 2014:2, 277-284

Huang JX, Blaskovich M, Pelingon R, Ramu S, Kavanagh A, Elliott A, Butler MS, Montgomery AB, Cooper MA Mucin Binding Reduces Colistin Antimicrobial Activity Antimicrob. Agents Chemother 2015 59:5925-5931 Marin H Kollef, Jean-Damien Ricard, Damien Roux, Bruno Francois, Eleni Ischaki, Zsolt

Rozgonyi, Thierry Boulain, Zsolt Ivanyi, Gál János, Denis Garot, Firas Koura, Epaminondas Zakynthinos, George Dimopoulos, Antonio Torres, Wayne Danker, A Bruce Montgomery A RANDOMIZED TRIAL OF THE AMIKACIN FOSFOMYCIN INHALATION SYSTEM FOR THE ADJUNCTIVE THERAPY OF GRAM-NEGATIVE VENTILATOR-ASSOCIATED PNEUMONIA: IASIS TRIAL. Chest 2016 Nov 24. Epub 2016 Nov 24.

Sime FB, Johnson A, Whalley S, Santoyo-Castelazo A, Montgomery AB, Walters KA, Lipman

J, Hope WW, Roberts JA Pharmacodynamics of Aerosolized Fosfomycin and Amikacin

against Resistant Clinical Isolates of Pseudomonas aeruginosa and Klebsiella

pneumoniae in a Hollow-Fiber Infection Model: Experimental Basis for Combination

Therapy. Antimicrob Agents Chemother. 2016, 61:1763-16.

CHAPTERS

Montgomery AB, Hudson LD. The role of sepsis in the adult respiratory distress syndrome. In Sande MA, Hudson LD, Root RK, eds. Contemporary issues in infectious diseases, vol. 5. Newer concepts in pathogenesis and treatment of respiratory tract infections. Churchill Livingstone, Inc., New York, 1986.


Montgomery AB, Luce JM. Infection monitoring. In: Pierson DJ, ed. Respiratory Intensive Care. Dallas: Daedalus Enterprises, 1986.

Montgomery AB.Therapy and Management of Pneumocystis carinii Pneumonia in patients with the Acquired Immunodeficiency Syndrome. In:Volberding PA, Jacobson MA, 1988 AIDS Clinical Review. New York. Marcel Dekker, 1989

Montgomery AB.Therapy and Management of Pneumocystis carinii Pneumonia in patients with the Acquired Immunodeficiency Syndrome. In:Volberding PA, Jacobson MA, 1991 AIDS Clinical Review. New York. Marcel Dekker, 1991

Montgomery AB. Aerosolized Pentamidine for treatment and prophylaxis of Pneumocystis carinii Pneumonia in patients with the Acquired Immunodeficiency Syndrome. In: Hickey AJ, Pharmaceutical Inhalation Aerosol Technology. New York. Marcel Dekker, 1992


EXHIBIT B


LIST OF MATERIALS CONSIDERED

Exhibit No. Document

1001 U.S. Patent No. 9,402,845

1002 U.S. Provisional Application No. 60/748,468

1003 Prosecution history of U.S. Patent No. 9,402,845 (excerpted)

1007 U.S. Patent No. 8,226,975 (U.S. Patent Application No. 11/634,343)



1010 U.S. Patent Publication No. 2014/0072620 (U.S. Patent Application No. 14/080,922)

1014 U.S. Patent No. 8,673,349

1024 Finlay et al., “Regional lung deposition of nebulized liposome-encapsulated ciprofloxacin,” International Journal of Pharmaceutics, 167:121-127 (1998)

1025

Saiman et al., “Antibiotic Susceptibility of Multiply Resistant Pseudomonas aeruginosa Isolated from Patients with Cystic Fibrosis, Including Candidates for Transplantation,” Clinical Infectious Diseases, 23:532-537 (September 1996)

1026 Zhanel et al., “A Critical Review of the Fluoroquinolones Focus on Respiratory Tract Infections,” Drugs, 62 (1), pp. 13-59 (2002)

1027

Ciofu et al., “Occurrence of Hypermutable Pseudomonas aeruginosa in Cystic Fibrosis Patients is Associated with the Oxidative Stress Caused by Chronic Lung Inflammation,” Antimicrobial Agents and Chemotherapy, Vol. 49, No. 6, pp. 2276-2282 (June 2005)

1028

Gay et al., “In Vitro Activities of Norfloxacin and Ciprofloxacin Against Mycobacterium tuberculosis, M. avium Complex, M. chelonei, M. fortuitum, and M. kansaii,” Antimicrobial Agents and Chemotherapy, Vol. 26, No. 1, pp. 94-96 (July 1984)

1029

Bakker-Woudenberg et al., “Ciprofloxacin in Polyethylene Glycol-Coated Liposomes: Efficacy in Rat Models of Acute or Chronic Pseudomonas aeruginosa Infection,” Antimicrobial Agents and Chemotherapy, Vol. 46, No. 8, pp. 2575-2581 (August 2002)

1030 International Patent Pub. No. WO2008/063341



1031 NebuPent® on Drugs@FDA (https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process) (last visited April 24, 2017)

1032 Prescribing Information for TOBI® (October 2015)

1033 Prescribing Information for CAYSTON® (2014)

1034 Betageri et al., Liposome Drug Delivery Systems, (Technomic Publishing Co. ed., 1993) (excerpted)

1035 Cullis et al., “Liposomes as Pharmaceuticals,” Liposomes From Biophysics to Therapeutics, pp. 39-72 (M. Ostro ed., 1987)

1036

Fenske et al., “Encapsulation of weakly-basic drugs, antisense olidonucleotides, and plasmid DNA within large unilamellar vesicles for drug delivery applications,” Liposomes Second Edition A Practical Approach, pp. 167-191 (V. Torchilin et al. eds., 2003)

1037 Cullis et al., “Generating and loading of liposomal systems for drug-delivery applications,” Advanced Drug Delivery Reviews, 3, pp. 267-282 (1989)

1038 Amikacin – DrugBank (https://www.drugbank.ca/drugs/DB00479) (last visited April 14, 2017)

1039 Ciprofloxacin – DrugBank (https://www.drugbank.ca/drugs/DB00537) (last visited April 14, 2017)

1040 Yu et al., “The Effect of Temperature and pH on the Solubility of Quinolone Compounds: Estimation of Heat of Fusion,” Pharmaceutical Research, Vol. 11, No. 4, pp. 522-527 (1994)

1041

Asthma Center website (http://www.theasthmacenter.org/index.php/disease_information/asthma/using_special_devices/nebulizer_instructions/) (last visited April 14, 2017)

1042 Cipolla et al., “Assessment of aerosol delivery systems for recombinant human deoxyribonuclease,” S.T.P. Pharma Sciences, 4(1), pp. 50-62 (1994)

1043 Sangwan et al., “Aerosolized Protein Delivery in Asthma: Gamma Camera Analysis of Regional Deposition and Perfusion,” Journal of Aerosol Medicine, Vol. 14, No. 2, pp. 185-195 (2001)



1044 Niven et al., “Nebulization of Liposomes. I. Effects of Lipid Composition,” Pharmaceutical Research, Vol. 7, No. 11, pp. 1127-1133 (1990)

1045 U.S. Patent Publication No. 2004/0009126 to Pilkiewicz

1046

Wichert et al., “Amikacin liposomes: characterization, aerosolization, and in vitro activity against Mycobacterium avium-intracellulare in alveolar macrophages,” International Journal of Pharmaceutics, 78, pp. 227-235 (1992)

1047 Wong et al., “Liposome delivery of ciprofloxacin against intracellular Francisella tularensis infection,” Journal of Controlled Release, 92, pp. 265-273 (2003)

1048

Conley et al., “Aerosol Delivery of Liposome-Encapsulated Ciprofloxacin: Aerosol Characterization and Efficacy against Francisella tularensis Infection in Mice,” Antimicrobial Agents and Chemotherapy, Vol. 41, No. 6, pp. 1288-1292 (June 1997)

1049

Sunamoto et al., “Unexpected Tissue Distribution of Liposomes Coated With Amylopectin Derivatives And Successful Use In The Treatment Of Experimental Legionnaires’ Diseases,” Receptor-Mediated Targeting of Drugs, Vol. 82, pp. 359-371 (G. Gregoriadis et al. eds., 1984)

1050 Sunamoto et al., “Improved drug delivery directed to specific tissue using polysaccharide-coated liposomes,” Multiphase Biomedical Materials, pp. 167-190 (T. Tsuruta et al. eds., 1989)

1051 “Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route, Guidance for Industry and Review Staff, Good Review Practice,” October 2015

1052 Driscoll et al., “Intratracheal Instillation as an Exposure Technique for the Evaluation of Respiratory Tract Toxicity: Uses and Limitations,” Toxicological Sciences, 55, pp. 24-35 (2000)

1053 Hyde et al., “Anatomy, pathology, and physiology of the treacheobronchial tree: Emphasis on the distal airways,” J. Allergy Clin. Immunol., Vol. 124, No. 6, pp. S72-S77 (2009)

1054 Bruinenberg et al, “Inhaled Liposomal Ciprofloxacin: Once a Day Management of Respiratory Infections,” Respiratory Drug Delivery 2010, pp. 73-82 (2010)

1055 Cipolla et al., “Development of Liposomal Ciprofloxacin to Treat Lung Infections,” pharmaceutics, 8(1), 6 (March 1, 2016)



1056

Oh et al., “Formulation and Efficacy of Liposome-Encapsulated Antibiotics for Therapy of Intracellular Mycobacterium avium Infection,” Antimicrobial Agents and Chemotherapy, Vol. 39, No. 9, pp. 2104-2111 (September 1995)


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