UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_________________
`
`COMPLEX INNOVATIONS, LLC,
`Petitioner,
`
`v.
`
`ASTRAZENECA AB
`
`_________________
`
`U.S. Patent 7,759,328
`
`_________________
`
`DECLARATION OF MARTIN BEASLEY, Ph.D.
`
`1
`
`Complex Ex. 1012
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_________________
`
`COMPLEX INNOVATIONS, LLC,
`Petitioner,
`
`v.
`
`ASTRAZENECA AB
`
`_________________
`
`U.S. Patent 7,759,328
`
`_________________
`
`DECLARATION OF MARTIN BEASLEY, Ph.D.
`
`1
`
`Complex Ex. 1012
`
`
`
`
`I.
`
` Scope of Analysis ............................................................................................ 5
`
`A. Qualifications and Expertise ......................................................................... 7
`
`B. Legal Framework .......................................................................................... 9
`
`1.
`
`2.
`
`3.
`
`4.
`
`A Person of Ordinary Skill in the Art ..................................................... 9
`
`My Understanding of Claim Construction .............................................. 9
`
`My Understanding of Anticipation .......................................................10
`
`My Understanding of Obviousness .......................................................10
`
`II.
`
` Background ....................................................................................................11
`
`A.
`
`Inhalable Pharmaceutical Drug Formulations .............................................12
`
`1.
`
`2.
`
`3.
`
`The Original, Expired Symbicort Patent ...............................................14
`
`Transition of Budesonide and Formoterol to HFA ...............................15
`
`Mistry Disclosure of an HFA Formulation with PEG and PVP For
`
`Stability ............................................................................................................16
`
`4.
`
`Rogueda Stability Teachings with Precise References to PEG 1000,
`
`and PVP K25 ....................................................................................................18
`
`5.
`
`Development of the 328 Patent in Light of Prior Art Formulations .....19
`
`B. Background of the 328 Patent (Ex. 1001) ...................................................20
`
`
`
`2
`
`
`
`1.
`
`2.
`
`3.
`
`Stability in the 328 Patent Through PVP ..............................................22
`
`Valve Lubrication Through PEG in the 328 Patent ..............................26
`
`Brief Description of Challenged Claims of the 328 Patent ..................28
`
`III. Ground 1: Mistry Anticipates Claims 1, and 4-15 of the 328 Patent .............30
`
`A. Background of Mistry .................................................................................30
`
`B. Analysis of 328 Patent Claims 1, and 4-15 In View of Mistry ...................31
`
`Claim 1(a) ........................................................................................................31
`
`Claim elements 1(b) and 1(c) relate to formoterol and budesonide
`
`concentrations. .................................................................................................32
`
`Claim 1(b) ........................................................................................................33
`
`Claim 1(c) ........................................................................................................34
`
`Claim 1(d) ........................................................................................................35
`
`Claim 1(e) ........................................................................................................37
`
`Claims 4-7 ........................................................................................................40
`
`Claims 8-11 ......................................................................................................41
`
`IV. Ground 2: Rogueda Anticipates Claims 1, and 4-15 of the 328 Patent .........42
`
`A. Background of Rogueda ..............................................................................42
`
`B. Analysis of 328 Patent Claims 1, 4-15 in Light of Rogueda ......................43
`3
`
`
`
`
`
`Claim 1(a) ........................................................................................................43
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`Claim Elements 1(b) and (c) Anticipation – Rogueda Examples ....................44
`
`Claim Elements 1(b) and (c) Anticipation – Rogueda Control Samples .........47
`
`Claim 1(d) ........................................................................................................49
`
`Claim 1(e) ........................................................................................................50
`
`Claims 4-7 ........................................................................................................52
`
`Claims 8-11 ......................................................................................................53
`
`V. Ground 3: Mistry in View of Rogueda and Carling Renders Obvious Claims
`
`1, and 4-15 ................................................................................................................54
`
`A. Motivation to Combine ...............................................................................54
`
`Claim element 1(a) ...........................................................................................56
`
`Claim elements 1(b) and 1(c), and Claims 12-15 ............................................56
`
`Claim elements 1(d) and 1(e) ...........................................................................57
`
`Claims 4-11 ......................................................................................................60
`
`VI. Ground 4: Mistry in View of Rogueda, Meade, and Lewis Render Obvious
`
`Claims 2 and 3 ..........................................................................................................61
`
`VII. Conclusion ......................................................................................................64
`
`
`
`
`
`4
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`
`
`I, Martin Beasley, declare as follows:
`
`
`
`1.
`
`I have been retained by Hill, Kertscher & Wharton, LLP, which
`
`represents Complex Innovations, LLC, in connection with a petition for inter
`
`partes review of U.S. Patent No. 7,759,328, titled Composition for Inhalation
`
`(“328 Patent”). I understand that the 328 Patent is currently assigned to
`
`ASTRAZENECA AB.
`
`I. Scope of Analysis
`
`2.
`
`I have reviewed and am familiar with the 328 Patent, which issued to
`
`Govind, et al. on July 20, 2010. I understand that the 328 Patent includes 15
`
`claims. I also understand that the Petition for inter partes review that accompanies
`
`this Declaration seeks to cancel claims 1-15 of the 328 Patent. My analysis and
`
`opinions will focus on all challenged claims 1-15.
`
`3.
`
`I am advised that based on the patent law around filing dates and
`
`effective filing dates, my analysis should assume that the time of invention is, at
`
`the earliest, Feb. 1, 2002, the date of filing of the foreign application in Sweden,
`
`and that the Rogueda reference may be used as prior art under 102(a) and 102(b).
`
`4.
`
`I have reviewed and am familiar with various references, written
`
`materials, and literature, which are itemized below:
`
`a) Ex. 1001 U.S. Patent No. 7,759,328 to Govind, et al. (“328
`
`Patent”)
`
`5
`
`
`
`
`
`b) Ex. 1002
`
`File History to the 328 Patent (“File History”)
`
`c) Ex. 1003 U.S. Patent No. 6,123,924 to Mistry, et al. (“Mistry”)
`
`
`
`d) Ex. 1004 World Intellectual Property Organization (“WIPO”)
`
`International Publication No. WO 02/03958 to Rogueda (“Rogueda”)
`
`e) Ex. 1005 U.S. Patent No. 5,674,860 to Carling et al. (“Carling”)
`
`f) Ex. 1006 WIPO International Publication No. WO 99/06401 by
`
`inventor Ekström (“Ekström”)
`
`g) Ex. 1007 U.S. Pat. App. Publ. No. 2003/0018019 to Meade et al.
`
`(“Meade”)
`
`h) Ex. 1008 U.S. Pat. No. 8,142,763 to Lewis et al. (“Lewis”)
`
`i) Ex. 1009 News Articles about Loughborough AstraZeneca
`
`Research and Development
`
`j) Ex. 1010 Company History Website of Formulaction
`
`k) Ex. 1011 Curriculum Vitae of Martin Beasley, Ph.D.
`
`5.
`
`I have been asked to consider how a person of ordinary skill in the art
`
`(“POSITA”) would have understood the claims subject to inter partes review in
`
`light of the disclosure of the 328 Patent. I also have been asked how a POSITA
`
`would have understood and applied various references including the Mistry patent,
`
`the Rogueda WIPO publication, the Meade patent application publication, and the
`
`Lewis patent.
`
`
`
`6
`
`
`
`6.
`
`I am being compensated at my standard hourly rate of $400 dollars
`
`per hour for regular consulting. My compensation is not dependent on the outcome
`
`of this inter partes review and in no way affects the substance of my testimony in
`
`this matter.
`
`A. Qualifications and Expertise
`
`7. My resume/curriculum vitae is attached to this declaration as
`
`Exhibit 1012. I hold a doctoral degree (Ph.D.) in Pharmaceutical Sciences granted
`
`by the University of Mississippi in 1985, as well as a Master of Science in
`
`Pharmaceutics and Bachelor of Science in Pharmacy, granted by the University of
`
`Mississippi in 1981 and Auburn University in 1974, respectively. As reflected in
`
`Exhibit 1012, for over thirty-five (35) years, I have been active in the field of
`
`pharmacy, with over twenty-five (25) active years in pharmaceutical drug
`
`development.
`
`8.
`
`From 1985 to 1987, as a Senior Scientist in Sterile Products
`
`Formulation Research for Schering-Plough Corporation, I conducted formulation
`
`development of small molecules and recombinant proteins. I worked on line
`
`extension development for over-the-counter nasal sprays, both squeeze bottle and
`
`pump spray. Additionally, I prepared stability reports and development reports for
`
`IND/NDA submissions.
`
`
`
`7
`
`
`
`9.
`
`From 1991 to 1997 I served as Senior Manager, Formulations
`
`Development Laboratory (FDL) with the pharmaceutical company AAI
`
`International. In that position, I coordinated and directed product development,
`
`working with up to 18 formulation scientists for IND/NDA, NADA, and ANDA
`
`dosage forms, including an anti-asthma inhalation formulation. Around this time I
`
`also led a project supervising a formulation technician during formulation
`
`development of an over-the-counter pressurized aerosol canister containing a
`
`polymer, active drug, and other excipients dispersed in propellant. The product was
`
`targeted for treatment of mild acne. This included stability protocols and oversight
`
`of a contract aerosol manufacturer that compounded, filled, and finished the
`
`canisters. My work from 1985 to 1987, and 1991 to 1997, over all, included over
`
`two years of respiratory drug delivery and development, and formulation work and
`
`stability studies.
`
`10. From 2001 to 2011, while working as a Director and Senior Director
`
`in Pharmaceutical Development for King Pharmaceuticals Research and
`
`Development, Inc., I conducted on-site due diligence at Aventis (Holmes Chapel,
`
`UK) and SkyePharma (Switzerland), evaluating both documentation and the
`
`manufacturing sites for potential licensing of their respective pressurized metered
`
`dose inhalers for treatment of asthma and chronic obstructive pulmonary disorder
`
`to augment King’s product portfolio.
`
`
`
`8
`
`
`
`11.
`
`I am currently a Pharmaceutical Development Consultant and I
`
`provide expert pharmaceutical and patent opinions to clients investigating
`
`therapeutic product and drug development for a variety of illnesses and conditions.
`
`I also currently serve as Scientific Advisory Board Member for NextGen
`
`Development Group LLC.
`
`B. Legal Framework
`
`1.
`
`12.
`
`A Person of Ordinary Skill in the Art
`
`I have been advised and understand that a person having ordinary skill
`
`in the art (“POSITA”) is presumed to be aware of all pertinent art, thinks along
`
`conventional wisdom in the art, and is a person of ordinary creativity. With this
`
`understanding, a POSITA at the time of the invention claimed in the 328 Patent is
`
`a person holding a Bachelor of Science degree (or an equivalent) in chemistry,
`
`pharmacy or a related field with at least two years of relevant experience in
`
`respiratory drug delivery and development, including formulation work and
`
`stability studies. I am a POSITA under this definition based on my qualifications
`
`and expertise as described above in paragraphs 7-11, and in my CV attached as Ex.
`
`1011.
`
`2. My Understanding of Claim Construction
`
`13.
`
`I have been advised and understand that the claims are to be given
`
`their broadest reasonable construction in light of the specification as it would be
`
`
`
`9
`
`
`
`read by a POSITA at the time of invention. I believe that all of the terms of the
`
`claims I have examined have plain and ordinary meanings to a POSITA and no
`
`construction of these terms is necessary.
`
`3. My Understanding of Anticipation
`
`14.
`
`I have been advised and understand that the claims are anticipated
`
`when a single piece of prior art teaches each and every limitation of a particular
`
`claim in a single embodiment. I understand that the prior art is viewed by a
`
`POSITA at the time of filing of the patent at issue, here the 328 Patent. Also,
`
`limitations within a claim may be unexpressed but still inherent within the
`
`specification. Such inherent limitations are only anticipatory if they are necessarily
`
`present within the prior art embodiment. Finally, I understand that if a prior art
`
`reference has broader ranges than the patent at issue, and if the prior art reference
`
`provides some evidence of the criticality of the prior art invention at and inside
`
`those broad ranges, then there is sufficient disclosure for anticipation.
`
`4. My Understanding of Obviousness
`
`15.
`
`I have been advised and understand that a claimed invention is
`
`unpatentable if the differences between the invention and the prior art are such that
`
`the subject matter as a whole would have been obvious to a POSITA at the time
`
`the invention was made to which the subject matter pertains.
`
`
`
`10
`
`
`
`16.
`
`It is my understanding that obviousness is a question of law based on
`
`underlying factual findings: (1) the scope and content of the prior art; (2) the
`
`differences between the claims and the prior art; (3) the level of skill in the art; and
`
`(4) objective considerations of nonobviousness.
`
`17.
`
`I understand that for one or more references to render the claimed
`
`invention obvious, a POSITA must have a sufficient reason to combine the
`
`teachings of the references to arrive at the claims. I further understand that a basis
`
`to combine teachings from the references need not be stated expressly in any prior
`
`art reference. However, there must be an articulated reason with rational
`
`underpinnings to support a motivation to combine teachings.
`
`18.
`
`I understand that, when considering whether a patent claim is obvious,
`
`a POSITA should consider whether a teaching, suggestion, or motivation to
`
`combine the references exists so as to avoid impermissibly applying hindsight.
`
`
`
`II. Background
`
`19.
`
`In the late 1980s, policymakers came to understand that
`
`chlorofluorocarbons (CFCs) that were released into the atmosphere after being
`
`used as disposable propellants in a number of applications had a detrimental effect
`
`on the earth’s ozone layer. Accordingly, pharmaceutical companies were faced
`
`with legal pressures to reformulate inhaled drugs with non-CFC ingredients. In the
`
`
`
`11
`
`
`
`1990s and early 2000s, many of the reformulations took place in Leicestershire,
`
`England, where several pharmaceutical reformulation inventors resided, from at
`
`least two different companies. As I describe below, two sets of inventors, different
`
`from those of the 328 Patent, actually discovered and published non-CFC
`
`reformulations including formoterol and budesonide as APIs over a year before the
`
`effective filing date of the 328 Patent. One publication is a patent that issued in
`
`2000 and the other is an international application published by WIPO in early
`
`2002. Each reference anticipates all of the 328 Patent’s independent claims, and
`
`the WIPO reference anticipates all of the independent claims and all but two of the
`
`dependent claims.
`
`A. Inhalable Pharmaceutical Drug Formulations
`
`20. Pressurized metered-dose inhaler (pMDI) products were introduced
`
`into the market by the pharmaceutical industry in 1956 (3M Riker) for treatment of
`
`asthma and related diseases. The main propellant in this legacy pMDI and
`
`pharmaceutical competitors’ pMDIs was CFC, and specifically CFC-12.
`
`21. Approximately 30 years later, policymakers came to understand that
`
`CFCs were contributing to the depletion of the earth’s ozone layer, and, if not
`
`replaced in products distributed worldwide, would have grave consequences on
`
`both the environment and human health. As a result, the Montreal Protocol was
`
`agreed upon on 16 September 1987 and implemented on 01 January 1999. Based
`
`
`
`12
`
`
`
`on the schedule for complete discontinuation of CFC production and availability to
`
`the supply chain for incorporation into products, pharmaceutical industry scientists,
`
`inventors, and academic scientists undertook reformulation of pMDI’s with
`
`alternate propellants (e.g., hydrofluorcarbons or HFCs, usually referred to as
`
`hydrofluroalkanes or HFAs) well before the 01 January 1999 implementation date.
`
`22. Many of these reformulations have been patented. This is aptly
`
`captured in the abstract from the 1999 article “Non-CFC Metered Dose: the patent
`
`landscape”:
`
`There have been many patent applications to the European Patent
`Office over the past decade involving the transition of pressurised
`metered dose inhalers from the CFCs to non-CFC propellants. In
`addition to those where formulations are changed, there are those
`relating to specific drugs or drug classes, processes of manufacture and
`modifications to the container/closure system. Many of these have been
`opposed, usually on the grounds of obviousness. However, due to the
`length of time for the opposition process and the fact that there are few
`non-CFC pressurised inhalers on the market yet, the complete picture
`of which patents are valid are yet to unfold.
`
`(P. Bowman and D. Greenleaf, International Journal of Pharmaceutics, Vol.
`
`186, Issue 1, pp. 91-94 (September 10 1999, pp. 91-94) (emphasis added).)
`
`23. A POSITA, forced by the elimination of the CFC propellants from
`
`legacy products, would have successfully reformulated pMDI products by
`
`incorporating HFAs with known, generally accepted as safe pharmaceutical
`
`excipient(s) of various molecular mass, in various combinations and
`
`concentrations, in compatible package component systems (container, valve,
`13
`
`
`
`
`
`actuator, etc.) to deliver stable products suitable for intended therapeutic use and
`
`approval by regulatory agencies.
`
`B. Overview of the Combination HFA, Budesonide, and Formoterol
`
`Patents
`
`24. The 328 Patent simply is a formulation of “Symbicort,” a drug that
`
`originally was formulated using CFCs. However, the elements of the 328 patent all
`
`were disclosed in the pertinent prior art. As discussed below, the 328 Patent is
`
`nothing novel.
`
`1.
`
`The Original, Expired Symbicort Patent
`
`25. The drug known as Symbicort, which was filed as a trademark in
`
`2001 according to the USPTO, has been linked to several patents. By far the most
`
`important patent covering Symbicort was U.S. Pat. No. 5,674,860 (foreign filing
`
`date in 1991; hereinafter “Carling”, Ex. 1005), which recently expired. The Carling
`
`patent was a formulation developed when CFCs were still acceptable, and it
`
`covered the combination of active pharmaceutical ingredients (“APIs”) that is at
`
`the root of the novelty of Symbicort, i.e., combining the corticosteroid budesonide
`
`and the bronchodilator formoterol for the treatment of respiratory disorders such as
`
`asthma.
`
`26. As with so many other inhalable pharmaceutical formulations, the
`
`original Symbicort formulation, described in the now-expired Carling patent,
`
`
`
`14
`
`
`
`underwent the same transition from CFC to HFA propellant. Initially, the Carling
`
`patent taught CFCs—“The propellants used may be chlorofluorocarbons of
`
`different chemical formulae.” (ibid., 4:4-5). The specification further disclosed the
`
`“most frequently used chlorofluorocarbon propellants.” (ibid., 4:5-10). As with
`
`most inhalable pharmaceutical formulations, if not all of them, stability was a
`
`concern even for Carling. (e.g., ibid., 4:10-14). Here, Carling taught “[l]ow
`
`concentrations” of a “surfactant” for stability. (ibid., 4:10). As will be shown, later
`
`in development the particular surfactant that improved stability in prior art HFA
`
`formulations was PVP, an otherwise common excipient for improving stability.
`
`(See, e.g., Ex. 1002 (File History of 328 Patent) at p. 288 (stating from Handbook
`
`of Pharmaceutical Excipients, published in 2000, that povidone, also known as
`
`PVP, “is additionally used as a suspending, stabilizing, or viscosity-increasing
`
`agent in a number of topical and oral suspensions and solutions”).
`
`Transition of Budesonide and Formoterol to HFA
`
`2.
`27. A further iteration of the combination of budesonide and formoterol is
`
`disclosed in the published WIPO application, WO 99/64014, originally filed in
`
`1998 and invented by Ekström, apparently an AstraZeneca employee. In Ekström,
`
`the formoterol and budesonide APIs are taught as combined together in a broad
`
`ratio for an inhalable pharmaceutical formulation, i.e., 1:1 to 1:100 by molecular
`
`weight. (See Ekström, Ex. 1006, p. 8:1-3; p. 12:11-12 (dependent Claim 2)). Here,
`
`
`
`15
`
`
`
`given the later date compared to Carling, and given the publication of Ekström in
`
`1999—the year the Montreal Protocol took effect—the Ekström disclosure teaches,
`
`in addition to a dry powder embodiment, both CFCs and HFAs for propellants:
`
`“The propellants which can be used include chlorofluorocarbons, hydrocarbons or
`
`hydrofluorocarbons.” (ibid., p. 6:25-26). However, the HFA propellants, including
`
`heptafluropropane, i.e., HFA 227, were apparently “[e]specially preferred” over
`
`the CFCs. (ibid., p. 6:26-30). Again, surfactants, excipients, and lubricants were
`
`taught, as well as a “stabilizing agent,” but nothing as specific as PVP or PEG.
`
`(ibid., p. 6:30).
`
`3. Mistry Disclosure of an HFA Formulation with PEG and PVP For
`Stability
`
`28.
`
`In between the filing dates of Ekström and Carling, employees from
`
`the company known as Fisons PLC, a former competitor of AstraZeneca (before
`
`the merger of Astra and Zeneca), filed in 1995 its own application of an HFA
`
`inhalation formulation for respiratory disorders. However, apparently soon after
`
`filing, and also in 1995, Astra, the precursor to AstraZeneca, purchased the
`
`intellectual property rights to Fisons’ non-CFC respiratory products and delivery
`
`devices, including Fisons’ R&D facility in or near Loughborough in Leicstershire,
`
`England. (Ex. 1009). The 1995 Fisons application issued in 2000 as U.S. Pat. No.
`
`6,123,924 (Exhibit 1003, “Mistry”), and is now likely owned by AstraZeneca,
`
`
`
`16
`
`
`
`although no ownership by AstraZeneca is publicly recorded at the USPTO as of the
`
`time of this writing.
`
`29. The Mistry patent teaches a pressurized aerosol inhalation
`
`composition with HFA. The medicament includes the combination of inhaled
`
`steroids and bronchodilators, and budesonide and formoterol are both listed as
`
`examples in these categories. (ibid., 3:27-42). A POSITA reading Mistry would
`
`understand that “formoterol” as a “medicament” in Mistry (ibid.) would include
`
`formoterol fumarate dihydrate. This would be known to a POSITA at least through
`
`Carling, which teaches a medicament version of formoterol as formoterol fumarate
`
`dihydrate. (See, e.g., Ex. 1005, 5:36-38).
`
`30. The HFA formulation taught by Mistry was a direct result of the
`
`external industry pressure to move away from CFCs and solving the problem of
`
`finding “suspending agents which are soluble in [HFAs] and capable of stabilising
`
`medicament suspensions.” (ibid., 1:24-36). Upon issuance in 2000, Mistry had
`
`disclosed and claimed a stable formulation of formoterol and budesonide with
`
`HFA, PVP and PEG. As taught by Mistry, the PEG can double as an excipient and
`
`a valve lubricant. (e.g., ibid., 2:30-37; 2:43-47). Mistry “[s]urprisingly” found that
`
`“certain polymers are both soluble in the aerosol propellants and capable of
`
`stabilising medicament compositions” (ibid., 1:39-41)—in particular, the
`
`stabilizing polymer taught by Mistry includes PVP at a range of K values and
`
`
`
`17
`
`
`
`concentrations. (ibid., 2:3-11). A POSITA would understand that PVP is, or can act
`
`like, a surfactant. Thus, following the progression from the Carling patent to
`
`develop more stable formulations, and Carling’s identification of surfactants as
`
`stabilizers, Mistry pursued more research into such surfactants for the original
`
`budesonide and formoterol formulations, and ended up selecting PVP for that
`
`stabilization function.
`
`4.
`
`Rogueda Stability Teachings with Precise References to PEG 1000,
`and PVP K25
`
`31.
`
`In 2000, the same year that Mistry issued, AstraZeneca filed a PCT
`
`application from Great Britain, which WIPO published on January 17, 2002, WO
`
`02/03958 (Ex. 1004, “Rogueda”). The inventor Rogueda’s address is listed as the
`
`AstraZeneca R&D facility in Loughborough in Leicestershire, England, which
`
`AstraZeneca bought from Fisons PLC where the Mistry invention was developed.
`
`Between the foreign filing of Rogueda in Great Britain in 2000, and the WIPO
`
`filing in 2001, a “Symbicort” trademark was filed at the USPTO, although other
`
`Symbicort trademarks had been previously filed. (Rogueda refers to
`
`“SymbicortTM” but it is unclear which trademark filing this refers to. (ibid., p.
`
`2:5)).
`
`32. By this time, usage of HFA formulations had been confirmed within
`
`the industry, so the transition from CFCs to HFAs is not even mentioned in
`
`Rogueda as it is in the other references. However, “[l]ong standing problems”
`
`
`
`18
`
`
`
`remained in the HFA formulations, in particular stability of the inhalable
`
`pharmaceutical suspension. (e.g., ibid., p. 2:6-8). Rogueda teaches that a polar
`
`fluorinated molecule could be combined with the HFA medicament formulation
`
`with certain suitable excipients to achieve an “increase of phase separate times
`
`(creaming or sedimentation),” which a POSITA would understand to be an
`
`increase in the stability of the formulation. (ibid., p. 2:10-12). The suitable
`
`excipients taught by Rogueda to improve stability include three PVP compounds,
`
`PVP K25, Plasdone K-29/32, and PVP K30 (e.g., ibid., p. 16).
`
`33.
`
`In so disclosing the polar fluorinated molecule invention, Rogueda
`
`also taught an HFA Symbicort formulation using PVP K25 and PEG 1000. (See
`
`Grounds 2 and 3 below). In Rogueda’s examples and control samples, the
`
`reference even discloses exact concentrations for the PVP K25 and PEG 1000
`
`excipients, concentrations that match up precisely onto the 328 Patent’s claimed
`
`concentrations. (See Ground 2 and 3 below).
`
`5.
`
`The Development of the 328 Patent in Light of Prior Art Formulations
`
`34. Finally, this line of research led to the 328 Patent. The inventors of the
`
`328 Patent, Govind and Marlow, are also listed as from Leicestershire, likely from
`
`the same former Fisons R&D facility as Mistry and Rogueda and had the same
`
`goal of “physical suspension stability” in HFA formulations. (Exhibit 1001, 1:32-
`
`35). The 328 Patent discloses the same API combination of budesonide and
`
`
`
`19
`
`
`
`formoterol as previously taught in references such as Carling and Ekström.
`
`Ultimately, the 328 Patent borrows the PVP stability and PEG lubrication excipient
`
`selection, and concentrations, from Mistry and Rogueda, the predecessor inventors
`
`likely from the Loughborough R&D division who had apparently been working on
`
`increased stability HFA formulations for over a decade, and had published within
`
`the prior art that PVP was a top stability excipient selection.
`
`B. Background of the 328 Patent (Ex. 1001)
`
`35. The 328 Patent was filed in Sweden in 2002, but maintains at the
`
`earliest a USPTO effective date of January 29, 2003, i.e., its PCT filing date, for
`
`purposes of invalidating prior art. (See above, ¶ 3). Two of the grounds below
`
`show that the 328 Patent’s predecessor inventions from Loughborough, Mistry and
`
`Rogueda, anticipate the independent claims of the 328 Patent. And two more of the
`
`grounds below show that each and every patent claim of the 328 Patent was
`
`obvious, given the prior art progression of HFA and excipient stability
`
`formulations in the industry.
`
`36. The 328 Patent relates to a composition for inhalation comprised of
`
`formoterol fumarate dihydrate, budesonide, 1,1,1,2,3,3,3-heptafluoropropane,
`
`known by the 328 Patent as “HFA227,” polyvinyl pyrrolidone (“PVP”), and
`
`polyethylene glycol (“PEG”). As stated in the abstract, the patent is for “use in the
`
`treatment of respiratory diseases.” (Exhibit 1001, Abstract). The compositions of
`
`
`
`20
`
`
`
`the patent can be “inhaled from any suitable MDI [metered dose inhaler] device.”
`
`(ibid., 2:13-14). The 328 Patent concerns a combination of active pharmaceutical
`
`ingredients (“API”) budesonide and formoterol. Budesonide is a steroid medication
`
`commonly used for respiratory diseases like asthma. It is commonly combined
`
`with formoterol, a bronchodilator that relaxes muscles in the airway allowing for
`
`easier breathing. As discussed in Background Section A, legacy CFC budesonide
`
`and formoterol inhalers needed to be redesigned with new chemical propellants.
`
`37. The combination of budesonide and formoterol was known to the
`
`public by at least 1997, the year in which the presently expired Carling patent
`
`issued. The Carling patent is thought to be the first “Symbicort” patent, the abstract
`
`of which reads: “[e]ffective amounts of formoterol and/or a physiologically
`
`acceptable salt and/or solvate thereof and budesonide are used in combination for
`
`simultaneous, sequential or separate administration by inhalation in the treatment
`
`of an inflammatory respiratory disorder, such as asthma.” (Exhibit 1005, Abstract).
`
`I highlight that this original Symbicort patent teaches “formoterol and/or a
`
`physiologically acceptable salt and/or solvate thereof,” and specifically teaches
`
`formoterol fumarate dihydrate. (Ibid., Abstract; 3:37-38). Carling also teaches
`
`formoterol fumarate dihydrate mixed with budesonide. (Ibid., 3:61-62).
`
`38. PVP and PEG were also known to a POSITA prior to the filing date of
`
`the 328 Patent. Mistry taught PVP as a stabilizing polymer and PEG as a valve
`
`
`
`21
`
`
`
`lubricant at least when it issued as a patent in 2000, and it was filed in 1995 and
`
`claims priority back to 1992. (See Section II.3). Rogueda also taught a smaller
`
`subset of PVP and PEG molecules. Rogueda taught that PVP excipients helped in
`
`solving the goal of improved stabilization, and it was published in 2002, just over a
`
`year before the 328 Patent’s PCT filing date. (See Section II.4).
`
`39. The specification of the 328 Patent states that two methods were used
`
`to “evaluate physical suspension stability,” i.e., optical suspension characterization
`
`“OSCAR” and “TURBISCAN”. (Ex. 1001, 2:66-3:1). These methods can “semi-
`
`quantify” sedimentation and creaming rates and existed in the prior art. The
`
`OSCAR equipment can conduct “reproducible semi-quantification of metered dose
`
`inhaler suspension characteristics,” and the specification states that this method
`
`was known in the prior art. (ibid., 3:11-12, 3:38-45). TurbiscanTM is well known
`
`within the prior art to POSITAs, e.g., the MA2000, the same device used in the
`
`328 Patent, won awards in 1997 at the International Exhibition & Conferences for
`
`Instrumentation in New Orleans. (Ex. 1010).
`
`1.
`
`Stability in the 328 Patent Through PVP
`
`40. Proper stability is important in many drug formulations, and this can
`
`be achieved through suspension of particles by adding an excipient to reach an
`
`optimal viscosity. Viscosity is the fluid friction, or thickness or “stickiness” of a
`
`fluid or semi-fluid substance under sheer. A POSITA would understand that
`
`
`
`22
`
`
`
`sedimentation in a drug formulation suspension occurs in part when the density of
`
`the particles is greater than the rest of the formulation and in part when the
`
`viscosity is too low, causing the particles to fall out of the suspension and
`
`accumulate on the bottom of a vessel. Creaming occurs in part when the density of
`
`the particles is less than the rest of the formulation, also in part when the viscosity
`
`is too low, causing the particles rise to the top of the vessel. (e.g., Ex. 1001, 4:5-
`
`14). Thus, in the understanding of a POSITA, reaching the appropriate viscosity
`
`with PVP
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