UNITED STATES PATENT AND TRADEMARK OFFICE
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`ARGENTUM PHARMACEUTICALS LLC
`Petitioner
`v.
`CIPLA LTD.
`Patent Owner
`Patent No. 8,168,620
`Issue Date: May 1, 2012
`Title: COMBINATION OF AZELASTINE AND STEROIDS
`Inter Partes Review No.: IPR2017-00803
`SECOND DECLARATION OF DR. MAUREEN D. DONOVAN, Ph.D.
`
`Exhibit 1165
`IPR2017-00807
`ARGENTUM
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`Patent No. 8,168,620
`TABLE OF CONTENTS
`Introduction ....................................................................................................... 1
`I.
`The Basis For My Opinion ............................................................................... 1
`II.
`III. Cipla’s assertd meaning of “suitable for nasal administration” and “nasal
`spray” are MEANING OF “SUITABLE FOR NASAL
`ADMINISTRATION” AND “NASAL SPRAY” ............................................ 3
`IV. A POSA would not be dissuaded by the non-aqueous “liquid formulations”
`identified by Smyth because the cited references actually encourage a POSA 5
`V. Azelastine would be understood as compatible with MCC and CMC ............. 8
`VI. Cramer’s Example III, while not the focus of a POSA’s understanding,
`supports a POSA’s reasonable expectation of successfully combining
`azelastine hydrochloride and fluticasone propionate into an aqueous nasal
`spray. ............................................................................................................... 13
`A. Dr. Govindarajan’s recreations each showed physical stability, and Dr.
`Govindarajan’s tested recreation provided a nasal spray. .................... 14
`B.
`Dr. Herpin did not make and test any of Dr. Govindarajan’s examples
`because Dr. Herpin used a different HPMC. ........................................ 17
`C.
`Dr. Herpin’s flawed attempt at Dr. Govindarajan’s example produced a
`pH within the pH range stated by the’620 for a nasal spray “suitable for
`nasal administration,” a fact acknowledged by Dr. Smyth during his
`deposition. ............................................................................................ 18
`Each of the Cramer Example III recreations falls within accepted
`D.
`osmolality values for nasal sprays according to the art submitted by
`both Petitioner and Patent Owner – including art specifically relied
`upon by Dr. Smyth ............................................................................... 19
`Cipla’s “recreations” of Cramer Example III are not representative of
`E.
`the routine work of a POSA ................................................................. 20
`VII. Patent Owner has relied on views in opposition to Dr. Smyth’s when
`obtaining other patents claiming priority to the ’620 patent. ......................... 22
`VIII. The prior art expressly provides for Dymista’s preservative combination .... 24
`IX. Glycerine is a widely used excipient with known advantageous solubilizing
`properties as well as tonicity effects ............................................................... 28
`X. Meda’s efforts were not that of a POSA and therefore do not show “failure by
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`others,” especially when one of the two trials appears successful ................. 31
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`Patent No. 8,168,620
`I, Maureen Donovan, do declare as follows:
`I.
`Introduction
`1.
`I am over the age of eighteen (18) and otherwise competent to make this
`declaration.
`2.
`I have been retained as an expert witness on behalf of Argentum
`Pharmaceuticals LLC for a inter partes review (IPR) for U.S. Patent No. 8,168,620
`(Ex. 1001). I am being compensated for my time in connection with this IPR at my
`standard consulting rate, which is $400 per hour for any consulting and $600 per
`hour for any deposition appearances. I understand that my declaration accompanies
`a petition for inter partes review involving the above-mentioned U.S. Patent.
`II.
`The Basis For My Opinion
`3.
`In formulating my opinion, the documents I considered include Patent
`Owner’s Response (Paper 21; “POR”), Dr. Smyth’s Second Declaration (CIP2150),
`his deposition transcript (Ex. 1143), Dr. D’Addio’s Second Declaration (CIP2148)
`and his deposition transcript (Ex. 1141), Dr. Herpin’s Declaration (CIP2029), the
`documents cited in each of these, as well as other documents provided by Cipla and
`submitted as part of the Petitioner’s Reply.
`I understand that an obviousness analysis involves comparing a claim to
`4.
`the prior art to determine whether the claimed invention would have been obvious to
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`Patent No. 8,168,620
`a person of ordinary skill in the art (POSA) in view of the prior art, and in light of
`the general knowledge in the art. I also understand that when a POSA would have
`reached the claimed invention through routine experimentation, the invention may be
`deemed obvious. I understand that a finding of obviousness for a specific range or
`ratio in a patent can be overcome if the claimed range or ratio is proven to be critical
`to the performance or use of the claimed invention.
`5.
`I also understand that obviousness can be established by combining or
`modifying the teachings of the prior art to achieve the claimed invention. It is also
`my understanding that where there is a reason to modify or combine the prior art to
`achieve the claimed invention, there must also be a reasonable expectation of success
`in so doing. I understand that the reason to combine prior art references can come
`from a variety of sources, not just the prior art itself or the specific problem the
`patentee was trying to solve. And I understand that the references themselves need
`not provide a specific hint or suggestion of the alteration needed to arrive at the
`claimed invention; the analysis may include recourse to logic, judgment, and
`common sense available to a person of ordinary skill that does not necessarily
`require explication in any reference.
`6.
`I understand that when considering the obviousness of an invention, one
`should also consider whether there are any secondary considerations that support the
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`Patent No. 8,168,620
`nonobviousness of the invention. I understand from counsel that another expert has
`been retained to opine on secondary considerations not discussed in this declaration.
`Similar to my first declaration, counsel has informed me that because another expert
`has provided expert testimony on the obviousness of independent claims 1, 24, 25, I
`am to assume obviousness of those claims.
`III.
`Cipla’s asserted meaning of “suitable for nasal administration” and
`“nasal spray” are ambiguous
`7.
`Cipla says that the claim terms “nasal spray” and “suitable for nasal
`administration” mean “pharmaceutical formulations that are tolerable to patients,
`that are homogeneous, and that can be suitably deposited onto the nasal mucosa.”
`POR, 8-9; Ex. 2150, ¶21. Further, Dr. Smyth testifies that
`Cipla also told the patent examiner that the term “suitable for nasal
`administration” was synonymous with the term “nasal spray,” as
`used in the ’620 patent. EX1002, 220 (“Likewise, independent
`claims 55 and 56 each recite a ‘nasal spray’…”).
`Ex. 2150, ¶21.
`8.
`However, all of the prior art references relied upon for Cipla’s
`obviousness grounds are expressly directed to nasal sprays suitable for nasal
`administration. E.g., Ex. 1007, 2:12-17; Ex. 1009, 32:57-60; Ex. 1010, 1; Ex. 1012,
`Abstract, 4-6. Indeed, Ex. 1007, Ex. 1009 and Ex. 1010 each teach commercially
`available nasal spray products. And Segal (Ex. 1012) and Cramer (Ex. 1011) each
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`teach aqueous compositions formulated as nasal drops or sprays that are both
`isotonic and pH adjusted that include both fluticasone and azelastine. Ex. 1012, 2, 3,
`6; Ex. 1011, 3:7-9, 27-30, 43-45.
`9.
`In addition, Cipla does not describe how long the claimed compositions
`must be homogenous. Must the formulation be homogenous perpetually, or 10 days,
`or three seconds, or does it merely have to be homogenous the instant it is made? If
`a formulation has settling but may easily be resuspended to become homogenous
`again, does it not meet Cipla’s standard? Cipla does not provide any of this
`information.
`10.
`Furthermore, Cipla does not indicate what osmolality values for a
`composition are “tolerable.” Cipla states an osmolality of 529 mOsm/kg is
`“unacceptable” in dismissing the relevance of Cramer. Ex. 2150, ¶ 38. Cipla and
`Dr. Smyth provide no art reference to support this (Ex. 2150, ¶ 38) and, in fact, the
`reference on which they rely identifies 200-600 mOsm/kg as an acceptable
`osmolality range (Ex. 2112, 19). Somehow, despite the art, 529 mOsm/kg is outside
`what Cipla considers tolerable. Yet Cipla does not provide a mOsm/kg range that is
`acceptable, only venturing to state that one particular value – 300 mOsm/kg – is
`acceptable.SeeEx. 2150, ¶38.
`11. Cipla does not provide an unambiguous statement of what time period
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`and situations should be considered for “homogeneous” and does not provide an
`unambiguous statement of what range in mOsm/kg is “tolerable” according to the
`claims of the ’620 patent. See Ex. 2150, ¶23. All that Cipla tells us is that art is not
`relevant or applicable because it does not meet these undisclosed standards. Under
`such terms one would have to contact Cipla, formulation by formulation, to ever
`know if a particular formulation met the claims of the ’620 patent.
`IV.
`A POSA would not be dissuaded by the non-aqueous “liquid
`formulations” identified by Smyth because the cited references
`actually encourage a POSA
`12. A POSA would not be dissuaded in combining fluticasone with another
`active ingredient in an aqueous system. Dr. Smyth claims CIP2111 and CIP2004
`undercuts a POSA’s motivation to combine fluticasone with another active
`ingredient in a “liquid formulation,” where he relies on discussions for non-aqueous
`liquid systems. CIP2150, ¶¶ 34-35. What Dr. Smyth ignores is that CIP2044 even
`describes the drug-containing complexes formed in a non-aqueous liquid system as
`avoiding deposition (CIP2044, 2), and, importantly, ignores that CIP2111 describes
`that in an aqueous system the complex was even better at avoiding deposition
`(CIP2111, 9-10).1
`
`1 While these references make many statements about potential molecular
`interactions, I am not stating that this particular mechanistic description is accurate –
`rather, I discuss how the references expressly contradict the assertions made by Cipla
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`13. Dr. Smyth relies on discussions from CIP2044, but does not address
`that the liquid used in the studies described in this reference is CFC-113 – a
`chlorofluorocarbon. CIP2044, 1-2. Moreover, this reference explicitly states that
`“The hetero-aggregation [in the chlorofluorocarbon media] results in
`reduced drug deposition onto the MDI surfaces as compared with that
`observed with the individual drug formulations. This phenomenon
`could be an advantage from a pharmaceutical point of view, i.e. the
`combination formulation shows a decrease in the total loss of the
`drugs due to deposition on to the internal surfaces of the MDI.”
`CIP2044, 2. The study in CIP2044 was directed to further exploring this
`heteroaggregation behavior in the chlorofluorocarbon media. Id., 2, 10. While
`noting “creaming” in the chlorofluorocarbon solvents – where the drug particles
`migrate to the air/liquid surface of the sample resulting in a decreased drug
`concentration at the bottom of the sample over time – these experiments did not
`attempt to re-suspend the particles.Id., 9. The authors found that in CFC-113 “[t]he
`interparticulate binding between salmeterol xinafoate and fluticasone propionate is a
`reversible process” – i.e., there was no irreversible caking in this solvent.Id., 8. Dr.
`Smyth avoids these explicit discussion of favorable aspects of the non-aqueous
`
`when citing to these references.
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`Patent No. 8,168,620
`inhaler system to focus on “aggregation,” implying any aggregation is discouraging
`– which, as discussed below, it is not.
`14. Dr. Smyth provides no discussion or explanation why a POSA would
`look to a non-aqueous solvent, or why a POSA would rely on information provided
`from a non-aqueous solvent-based pulmonary inhaler when considering an aqueous
`nasal spray system. Dr. Smyth simply cites claim 5 of the ’620 patent for “aqueous
`suspension” to somehow justify his reliance on the chlorofluorocarbon solvent of
`CIP2044. Ex. 2150, ¶ 34. However, his cited references themselves expressly state
`that the solvent medium is important in determining the behavior of the combination.
`CIP2044, Abstract, 5, 6, 10.
`15. Moreover, Dr. Smyth ignores teachings of CIP2111 that contradict his
`assertion, where the authors describe that the complex of salmeterol and fluticasone
`propionate provides “less deposition” in aqueous media compared to the single,
`uncomplexed drug species. CIP2111 also explicitly describes the differences
`between the chlorofluorocarbon CFC-113 and an aqueous solvent for the
`combination of salmeterol and fluticasone propionate. CIP2111, 9-10.
`16.
`Therefore, while Dr. Smyth cites to CIP2111 to support his proposition,
`he conspicuously ignores this statement and how it undercuts his arguments,
`especially in equating flocs with undesirable caking. CIP2150, ¶34. Instead,
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`CIP2111 states that the floc of salmeterol and fluticasone propionate provides “less
`deposition” as compared to the single, uncomplexed drug species – a desirable
`characteristic in a pulmonary inhaler.
`17.
`Therefore, a POSA would not be dissuaded from combining fluticasone
`with another active ingredient in an aqueous system.
`V.
`Azelastine would be understood as compatible with MCC and CMC
`18. Well before the ’620 patent, a POSA understood that MCC and CMC
`were compatible with hydrochloride salts of drugs. In particular, Avicel® RC 591 (a
`mixture of CMC and MCC) was known and understood to provide aqueous
`pharmaceutical suspensions that include monovalent cationic drugs. Instead of
`looking to the actual product guides for Avicel® RC 591 or in the art for particular
`discussion regarding Avicel® RC 591, Dr. Smyth instead relies solely on selected
`citations in Leiberman (CIP2113) to assert a POSA would regard azelastine
`hydrochloride as incompatible with MCC and CMC. CIP2150, ¶¶45-47. However,
`Dr. Smyth omits what Lieberman’s basis is for such statements.
`19.
`Lieberman’s citations are to the product guides from the producers of
`MCC and CMC – in particular, FMC for Avicel® RC 591. At these places,
`Lieberman cites to two references, both from the 1984: Cellulose Gums Chemical
`and Physical Properties, Hercules, Inc . Wilmington (1984), and B. Idson and A. J.
`Scheer, Suspensions. In: Problem Solver and Reference Manual. FMC Corp.,
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`Philadelphia (1984). CIP2113, 24, 61 n.51. Note that for Avicel® RC 591,
`Liebermann cites to a reference by FMC Corp., the manufacturer of Avicel® RC
`591. 20. A POSA would be well-versed on updated source material for Avicel®
`RC 591, including the 2001 FMC publication (Ex. 1146) discussing Avicel® RC
`591. This 2001 FMC publication at page 8 specifies CMC is incompatible with di-
`and trivalent salts.See also Ex. 1033, 10. A POSA would expect if an
`incompatability with monovalent cations existed, the 2001 FMC publication would
`list this along with the specific recitation of divalent salts and trivalent salts.
`Monovalent salts are not called out as problematic for Avicel® RC 591, but are for
`carbomer. Ex. 1146, 8.
`Further, a POSA would be aware of multiple aqueous suspension
`21.
`formulations that included at least one or more monovalent cationic drugs and
`utilizing a mixture of CMC and MCC such as Avicel® RC 591, including art
`describing aqueous nasal spray suspensions including both a monovalent cationic
`drug and Avicel® RC 591 (see infra).
`22.
`In 1972 aqueous suspensions including monovalent cationic drugs and a
`mixture of CMC and MCC were described in U.S. 3,636,200 (Ex. 1152). This
`reference discloses “stable” pharmaceutical suspensions that include a CMC/MCC
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`mix and hydrochloride salts of 8 different therapeutic agents. U.S. 3,636,200, 1:10-
`22; 3: 1-37. Examples 2-4 list specific aqueous suspensions utilizing Avicel® RC
`and 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine hydrochloride
`(Example 2), 4-(2-dimethylaminoethoxy)-N-(3,4,5-trimethoxybenzoyl)benzylamine
`hydrochloride (Example 3), and 2-chloro-9-(3-dimethylaminopropylidene)
`thioxanthene hydrochloride (Example 4), and Example 5 provides an aqueous
`suspension utilizing Avicel® RC and a monovalent cationic drug in the form of a
`hydrobromide salt. U.S. 3,636,200, 5:55 – 6:18.
`23. U.S. 5,196,436 (Ex. 1153), issued in 1993, provides five aqueous
`compositions that include varying amounts of dextromethorphan hydrobromide and
`Avicel® RC 591. U.S. 5,196,436, Examples I, IV, V, VI, and VII; claims 1, 5.
`24. U.S. 5,658,919 (Ex. 1154) issued in 1997, provides stable aqueous
`pharmaceutical suspensions that contain acetaminophen as well as at least one other
`pharmaceutical active, specifically naming at least four that are monovalent cationic
`drugs in aqueous solution: chloropheniramine maleate, diphenhydramine
`hydrochloride, dextromethorphan hydrobromide and pseudoephedrine
`hydrochloride. U.S. 5,658,919,2:10-16 ,4:21-36. This patent particularly highlights
`that pseudoephedrine hydrochloride, chlorpheniramine maleate, and
`dextromethorphan hydrobromide are generally in solution in the aqueous phase of
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`the suspension. U.S. 5,658,919, 4:37-42.
`25.
` In fact, U.S. 5,658,919provides a specific example of an aqueous
`suspension that includes three monovalent cationic drugs with Avicel® RC 591
`(Example 2) and three specific aqueous suspension examples with two monovalent
`cationic drugs together with Avicel® RC 591 (Examples 1 and 3-4).
`26. Moreover, an aqueous nasal spray suspension including both a
`monovalent cationic drug and Avicel® RC 591 was known. U.S. 6,565,832 (Ex.
`1155) was filed January 31, 2000 and issued on May 20, 2003. This patent
`highlights the use of Avicel® RC 591 “in compositions which otherwise have no
`suspended particulates, i.e., which compositions are [absent Avicel® RC 591]
`solutions.” U.S. 6,565,832, 3:54-56. Several aqueous nasal spray compositions that
`include oxymetazoline hydrochloride and Avicel® RC 591 are detailed. U.S.
`6,565,832, Examples 1-3.
`27. Based on the actual guidance provided by the manufacturer of Avicel®
`RC 591 and the multiple known aqueous suspensions utilizing Avicel® RC 591 with
`many different types of monovalent cationic drugs – including two or three
`monovalent cationic drugs in the same Avicel® RC 591 suspension – a POSA would
`not be dissuaded from using Avicel® RC 591 to provide an aqueous suspension that
`also included monovalent cationic drug. In fact, an aqueous nasal spray suspension
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`including a monovalent cationic drug and Avicel® RC 591 was already known in the
`art. U.S. 6,565,832, Examples 1-3.
`28. Azelastine hydrochloride in water below a pH of 8 provides a
`monovalent cationic drug. Ex. 1008, 2. As stated by Dr. Smyth, “ [i]n a
`pharmaceutical aqueous solution, the tertiary amine of azelastine will have a
`[singular] positive charge, thereby giving azelastine the behavior of a cationic drug.”
`CIP2150, ¶47. Therefore, once azelastine hydrochloride dissociates in solution, it
`would behave as a monovalent cationic drug.
`29.
`Therefore, a POSA would possess a reasonable expectation of success
`generating a suspension with both Avicel® RC 591 and azelastine hydrochloride
`(i) because an aqueous nasal spray suspension including a monovalent
`cationic drug and Avicel® RC 591 was already known in the art (U.S.
`6,565,832, Examples 1-3);
`(ii) because azelastine hydrochloride would be understood to dissociate to a
`monovalent cation in an aqueous media (supra);
`(iii)
`based on the actual guidance provided by the manufacturer of Avicel®
`RC 591( Ex. 1146), where Lieberman cites the same manufacturer for the
`proffered understanding of Avicel® RC 591 (CIP2113, 203);
` because multiple aqueous suspensions utilizing Avicel® RC 591 with
`(iv)
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`many different types of monovalent cationic drugs, as well as including
`two or three monovalent cationic drugs in the same Avicel® RC 591
`suspension, were well-known.
`Dr. Smyth fails to account for this understanding of a POSA, not even attempting to
`refer to the underlying citations of Lieberman or refer to art actually describing
`monovalent cationic drugs with Avicel® RC 591. Ex. 1143, 40:9-21.
`VI.
`Cramer’s Example III, while not the focus of a POSA’s
`understanding, supports a POSA’s reasonable expectation of
`successfully combining azelastine hydrochloride and fluticasone
`propionate into an aqueous nasal spray.
`30. Dr. Smyth opines that recreations of Cramer’s Example III by Dr. Ram
`Govindarajan, Dr. Matthew Herpin, and co-inventor Geena Malhotra were each (1)
`“physically unstable”, (2) “highly acidic,” (3) “unacceptably high osmolality.” Ex.
`2150, ¶ 41.
`31. Yet, Dr. Govindarajan’s recreations each showed physical stability. Ex.
`2030, 4 (¶ 13-14). Dr. Herpin’s report purports to make and test Dr. Govindarajan’s
`example tested for acceptability as a nasal spay, but this is not the case: Dr. Herpin
`used a different HPMC grade than used by Dr. Govindarajan. While Dr. Herpin
`immediately saw different results in the initial steps, neither Dr. Herpin nor Dr.
`Smyth seem to question this when concluding Dr. Govindarajan’s recreations were
`physically unstable and unsuitable as a nasal spray.
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`32. However, even Dr. Herpin’s flawed attempt at Dr. Govindarajan’s
`example produced a pH within the pH range stated by the ’620 patent as “suitable for
`nasal administration.” SeeEx. 1143, 79: 9-20.
`33.
`In addition, Dr. Govindarajan’s recreations, as well as each of the other
`Cramer Example III recreations, fall within accepted osmolality values for nasal
`sprays according to the art submitted by both Petitioner and Cipla – including art
`specifically relied upon by Dr. Smyth (Ex. 2150, ¶ 38 (citing to CIP2112,19)).
`While Dr. Smyth’s position is that these examples show unacceptable osmolality,
`Dr. Smyth has no citation but merely asserts it must be true. Ex. 2150, ¶ 38. Even
`Ms. Malhotra’s statements regarding unacceptable osmolality only rely on
`“preferred” ranges and simply states that the osmolality of her recreation is
`“undesirable.” Ex. 1002, 287 ((C)).
`A.
`Dr. Govindarajan’s recreations each showed physical stability, and
`Dr. Govindarajan’s tested recreation provided a nasal spray.
`34. Dr. Govindarajan’s recreations of Cramer’s Example III (which were
`submitted by Cipla) each were found to be physically stable. These three batches
`were 1345-004, 1345-008, and 1345-011. Ex. 2030, 24. For each batch, Dr.
`Govindarajan utilized Hypromellose, Type 2910, Pharmacoat 606. Ex. 2030, 27; see
`also Ex. 2150, ¶ 42 (Dr. Smyth acknowledging this is the HPMC used by Dr.
`Govindarajan); Ex. 2105, 4-6. As noted by Dr. Smyth, this grade of HPMC has an
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`apparent viscosity of 6 cP according to the USP method for determining viscosity.
`Ex. 2150, ¶ 42; Ex. 2105, 8.
`35. Dr. Govindarajan describes preparing Batch 1345-004 on pages 28-31,
`where HPMC was added to a pre-mixed solution of azelastine hydrochloride, sodium
`chloride, and benzalkonium chloride where during the addition the solution was
`stirred vigorously forming a vortex “to hydrate and disperse the hypromellose to
`yield a clear solution.” Ex. 2030, 30 (emphasis added). The remaining components
`were subsequently added as detailed by Dr. Govindarajan. Ex. 2030, 30-31.
`36. Upon forming the final suspension formulation it was stored overnight,
`after which Dr. Govindarajan identified a fine settled solid that “easily redispersed
`upon gentle agitation by overturning the vial 3-4 times” where the solid was “readily
`and uniformly resuspended.” Ex. 2030, 31.
`37. Batch 1345-008 was prepared by a different method than Batch 1345-
`004, but like Batch 1345-004 also presented a “clear solution” upon addition of
`hypromellose. Ex. 2030, 33. Upon forming the final suspension formulation, Dr.
`Govindarajan found that “settling of the suspended solid occurred over time, but the
`sediment was easily and uniformly resuspendable.” Ex. 2030, 34.
`38. Batch 1345-011 was a 500 mL preparation where, similar to the
`previous two batches, Dr. Govindarajan found settled solid was easily and readily
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`resuspended by gentle inversion of the container. Ex. 2030, 38. In this section Dr.
`Govindarajan also highlights that samples of 1345-004 and 1345-008 that were left
`undisturbed for 3 days had some sediment that was also easily and readily
`resuspended by gentle inversion of the container. Ex. 2030, 38.
`39. Batch 1345-011 was tested for spray delivery tested in a nasal spray
`pump where delivery by the spray pump was visually observed and the delivery
`pattern recorded on video. Ex. 2030, 39. Dr. Govindarajan included two videos of
`the mist produced in his report (Ex. 2030, 4 (¶ 14)), but Cipla conspicuously
`declined to provide these videos. Based on his observations and these videos, Dr.
`Govindarajan found that Batch 1345-011 “delivered a fine spray.” Ex. 2030, 4 (¶
`14); 39. Dr. Govindarajan also found that Batch 1345-011 had an osmolality of 529
`mOsm/kg. Ex. 2030, 39.
`40. Based on the data obtained from his recreations, Dr. Govindarajan
`concluded that such suspensions are acceptable as nasal sprays, where “[t]here was
`some settling, but no settling or sedimentation in the product that would make it
`pharmaceutically unacceptable” and that such suspensions “could be delivered as a
`fine spray using a nasal spray pump.” Ex. 2030, 4 (¶ 13-14). Indeed, these exact
`behaviors are cited by Dr. Smyth for a pharmaceutically acceptable suspension. Ex.
`2150, ¶ 35 (citing to Ex. 2113, 5; Ex. 2103, 12; 2104, 6-7).
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`B.
`Dr. Herpin did not make and test any of Dr. Govindarajan’s
`examples because Dr. Herpin used a different HPMC grade.
`41. Dr. Herpin purports to formulate and test Cramer Example III using
`three processes: the process of Cramer’s description, “the process Geena Malhotra
`describes in her August 12, 2011 declaration,” and “the first process Dr.
`Govindarajan used in his June 30, 2016 report.” Ex. 2029, 2 (¶ 6).
`42. However, Dr. Herpin does not use the grade of HPMC utilized by Dr.
`Govindarajan. Dr. Herpin uses an HPMC that has a viscosity of 3 cP in his single
`attempt to replicate Dr. Govindarajan’s first process. Ex. 2029, 3 (¶ 8-10). But this
`is clearly not correct, because Dr. Govindarajan used an HPMC with a viscosity of 6
`cP. Ex. 2030, 27; Ex. 2150, ¶ 42; Ex. 2105, 4-6. It is not clear how this was missed
`– in fact, Dr. Smyth admits that he developed Dr. Herpin’s protocols: “He followed
`protocols and procedures that I wrote out for the testing of Cramer Example III.”
`Ex. 2021, 171: 19-20. Nonetheless, the fact that Dr. Herpin did not use the correct
`grade of HPMC means that Dr. Herpin did not recreate Dr. Govindarajan’s first
`recreation.43.
`It seems warning signs that Dr. Herpin and Dr. Smyth had made a
`mistake were evident early on. Dr. Herpin, in attempting to follow Dr.
`Govindarajan’s procedure for Batch 1345-004, observes that in adding the
`hypromellose it “did not form a clear solution.” Ex. 2029, 52. This was prior to
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`Patent No. 8,168,620
`adding triamcinolone acetonide – the active pharmaceutical ingredient to be
`suspended.Id. Such a clear discrepancy with Dr. Govindarajan’s observations
`should have given Drs. Herpin and Smyth pause, especially because hypromellose
`has “high solubility” in water. Ex. 2105, 9. Instead, there is no discussion regarding
`this clear discrepancy.
`44.
`In addition, Dr. Herpin (and thus also Dr. Smyth) chose Dr.
`Govindarajan’s first process that resulted in Batch 1345-004 and did not attempt to
`generate Batch 1345-011, Dr. Govindarajan’s recreation that was used to test the
`ability to spray the composition. Ex. 2030, 28-31; 38-39. The reason for this
`avoidance is also unclear.
`45. Because Dr. Herpin’s testing was not performed on any of Dr.
`Govindarajan’s recreations, especially not the one used to test spray, Dr. Herpin’s
`testing does not contradict Dr. Govindarajan’s findings.
`C.
`Dr. Herpin’s flawed attempt at Dr. Govindarajan’s example
`produced a pH within the pH range stated by the’620 for a nasal
`spray “suitable for nasal administration,” a fact acknowledged by
`Dr. Smyth during his deposition.
`46. Dr. Herpin’s attempt at Dr. Govindarajan’s Batch 1345-004 exhibited a
`pH of 3.04. Ex. 2029, 53. The claims of the’620 patent do not state when in time
`the formulation must be suitable for nasal administration. While Dr. Smyth asserted
`that a pH of 3 was below the pH of an acceptable nasal formulation, claim 45 of the
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`’620 patent states that claim 1 formulation “suitable for nasal administration” may be
`“a pH from 3 to 7” (Ex. 1001, claims 1, 45). At his deposition, Dr. Smyth admitted
`such a pH range would have to be suitable for nasal administration. Ex. 1143, 79: 9-
`20. D.
`Each of the Cramer Example III recreations falls within accepted
`osmolality values for nasal sprays according to the art submitted by
`both Petitioner and Cipla – including art specifically relied upon by
`Dr. Smyth
`47. Dr. Smyth’s assertion that all the Cramer Example III recreations show
`unacceptable osmolality is not supported by the art. In fact, for this contention Dr.
`Smyth has no citation but merely asserts it must be true. Ex. 2150, ¶ 38. Dr.
`Smyth’s own reference identifies 200-600 mOsm/L as an acceptable osmolality
`range (Ex. 2112, 19), where Dr. Smyth admits the Cramer Example III recreations
`are within this range (Ex. 2150, 23 (fn. 10)). Even Ms. Malhotra’s statements
`regarding osmolality only rely on “preferred” ranges and simply states her recreation
`had an osmolality that was “undesirable.” Ex. 1002, 287 ((C)).
`48. While Dr. Smyth tries to allege that the side effects listed for Imitrex
`would be associated with Imitrex’s osmolality of 742 mOsm/kg (Ex. 2150, ¶ 38),
`Azelastin® Nasal Spray (Ex. 1008, 3148) and Flonase® Nasal Spray (Ex. 1010, 7)
`each exhibit the same side effects as do the placebo vehicle. Dr. Smyth’s association
`of these side effects with Imitrex’s osmolality lacks support in the art.
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`49.
`Each of the Cramer Example III recreations therefore exhibited
`osmolality values within ranges taught by the art of record – the same ranges a
`POSA would view as acceptable for a nasally administered pharmaceutical
`suspension.E.
`Cipla’s “recreations” of Cramer Example III are not representative
`of the routine work of a POSA
`50. Dr. Smyth tries to characterize the recreations of Cramer Example III as
`“routine modifications” (Ex. 2150, ¶¶36, 42) and that Cramer Example III could not
`provide a formulation suitable for nasal administration “even after routine
`modifications (Ex. 2150, ¶43). Thus, in addition to ignoring Dr. Govindarajan’s
`successful recreations, Dr. Smyth also incorrectly asserts the few recreation efforts
`he designed (carried out by Dr. Herpin) and the one sample by Ms. Malhotra are
`representative of the routine modifications that would be employed by a POSA.
`51. However, there are multiple routine modifications commonly employed
`by a POSA that were never attempted by Dr. Herpin or Ms. Malhotra (whose focus
`was recreation, not generating a successful formulation). Just four of these routine
`modifications are (i) modification of the HPMC by assessing multiple commercial
`grades of HPMC, (ii) modification of the amount of HPMC used, (iii) modification
`of the amount of sodium chloride used, and (iv) modification of the type of spray
`device employed – none of which was performed by Dr. Herpin or Ms. Malhotra.
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