`
`IPR2017-01648
`U.S. Patent No. 6,866,866
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`----------------------------------------------------------------------------------------------------
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`-----------------------------------------------------------------------
`Aurobindo Pharma USA Inc.
`
`Petitioners,
`v.
`Andrx Labs, LLC
`
`Patent Owners
`
`-----------------------------------------------------------------------
`
`Case No.: IPR2017-01648
`United States Patent No. 6,866,866
`-----------------------------------------------------------------------
`PETITIONER'S REPLY TO
`PATENT OWNER'S RESPONSE
`
`
`
`
`
`

`

`
`
`IPR2017-01648
`U.S. Patent No. 6,866,866
`
`I.
`
`TABLE OF CONTENTS
`INTRODUCTION ........................................................................................... 1
`A. The Limited Grounds of this Case ............................................................ 1
`B. Patent Owner's Unsupportable Attack on the Expertise of Dr.
`Akhlaghi .................................................................................................... 1
`THE PRIOR ART ............................................................................................ 5
`II.
`III. THE POSA WOULD BE MOTIVATED TO TARGET A MEAN TMAX
`RANGE OF THE CLAIMS IN A FORMULATION OF CHENG
`BASED ON TIMMINS ................................................................................... 8
`IV. THERE IS NO TEACHING AWAY FROM COMBINING CHENG
`AND TIMMINS ............................................................................................ 14
`V. A POSA WOULD HAVE A REASONABLE EXPECTATION OF
`SUCCESS IN COMBINING CHENG AND TIMMINS.............................. 16
`VI. AS THE PO ADMITTED THAT CLAIMS 3-5 AND 25 WERE NOT
`SEPARATELY PATENTABLE FROM CLAIM 1 IN THE SCIELE
`CASE, AND THE REMAINING DEPENDENT CLAIMS,
`INCLUDING THOSE RECITING THE CLAIMED RANGES OF 5.5-
`7.5 HOURS AND 6.0 TO 7.0 HOURS, WERE NOT ARGUED TO
`PROVIDE ANY INVENTIVE CONTRIBUTION OVER THE
`INDEPENDENT CLAIMS IN THE PO RESPONSE, NO
`DEPENDENT CLAIM SUPPORTS PATENTABILITY OVER
`INDEPENDENT CLAIM 1 ........................................................................... 20
`VII. AKHLAGHI DID NOT ENGAGE IN "HINDSIGHT REASONING" ........ 21
`VIII. THE OBJECTIVE INDICIA OF OBVIOUSNESS CITED BY
`DRESSMAN IN EXHIBIT 2010 DOES NOT SUPPORT NON-
`OBVIOUSNESS OF THE CHALLENGED CLAIMS ................................. 22
`IX. CONCLUSIONS ........................................................................................... 24
`
`
`
`i.
`
`

`

`TABLE OF AUTHORITIES
`
`
`
`
`Page(s)
`
`Federal Cases
`
`Cases
`
`Apple Inc. v. Samsung Elcs. Co.,
`2016 U.S. App. LEXIS 3432 (Fed. Cir. Feb. 26, 2016) ....................................................................... 22
`
`Eli Lilly & Co. v. Zenith Goldline Pharm., Inc.,
`172 F.Supp.2d 1060 (S.D. Ind. 2001) ................................................................................................... 23
`
`Garmin Int’l Inc. v. Cuozzo Speed Tech. Inc.
`IPR2012-0001 (November 13, 2013) ................................................................................................... 15
`
`Iron Grip Barbell Co. v. USA Sports, Inc.,
`392 F.3d 1317 (Fed. Cir. 2004) ............................................................................................................ 22
`
`KSR Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................................................. 16
`
`Medichem S.A. v. Rolabo S.I.,
`437 F.3d 1157 (Fed. Cir. 2006) ............................................................................................................ 14
`
`Meiresonne v. Google, Inc.,
`Case No. 16-7855 (Fed. Cir, March 2017) ........................................................................................... 15
`
`In re O’Farrell,
`853 F.2d 894 (Fed. Cir. 1988) .............................................................................................................. 16
`
`Par Pharm. Inc. v. Twi Pharms., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) ............................................................................................................ 18
`
`PharmaStem Therapeutics, Inc. v. ViaCell, Inc.,
`491 F.3d 1342 (Fed. Cir. 2007) ............................................................................................................ 16
`
`Sciele Pharma v. Lupin Ltd,
`684 F.3d 1253 (Fed. Cir. 2012) ..................................................................................................... passim
`
`In re Wands,
`858 F.2d 731 (Fed. Cir. 1988) .............................................................................................................. 18
`
`Statutes
`
`Hatch-Waxman Act .................................................................................................................................... 23
`
`i.
`
`

`

`
`
`
`Other Authorities
`
`37 C.F.R. 1.111, February 24, 2003, p. 8-p. 9 .............................................................................................. 6
`
`37 C.F.R. §1.111 ......................................................................................................................................... 13
`
`Sciele Oral Argument 2012-1228.mp3 at 19.36–21.29 available at
`http://www.cafc.uscourts.gov/oral-agrument-recordings/2012-2018/all .............................................. 11
`
`U.S. Patent No. 6,866,866 .................................................................................................................... passim
`
`
`ii.
`
`

`

`I.
`
`INTRODUCTION
`
`
`
`IPR2017-01648
`U.S. Patent No. 6,866,866
`
`A. The Limited Grounds of this Case
`By a Joint Motion to Limit the Petition (Paper 22), and the order granting the
`
`same by the Board (Paper No. 23), this inter partes review of U.S. Patent No.
`
`6,866,866 (the “’866 patent”) is now limited to Ground 3, obviousness of claims 1-
`
`25 over WO 99/47128 to Timmins ("Timmins") and WO 99/4715 to Cheng
`
`("Cheng") as set forth in Paper No. 12, Ground of Institution.
`
`B.
`
`Patent Owner's Unsupportable Attack on the Expertise of Dr.
`Akhlaghi
`As a diversion to distract attention from the fundamental weakness of Patent
`
`Owner's substantive validity arguments ("PO"), PO engages in a baseless attempt
`
`to unfairly disparage Dr. Akhlaghi's ("Akhlaghi") expertise, including by
`
`selectively and misleadingly citing to isolated snippets of her testimony taken out
`
`of context, elicited during a deposition in which PO's counsel badgered her by
`
`repetitively reframing the same basic line of questioning over and over again, to
`
`attempt to twist her answers.
`
`For example, PO urges that Akhlaghi "concedes that she is not an expert
`
`formulation development" to argue a "lack of expertise in this area undercut[ting]
`
`the value of her opinions" (Paper 25, 14:11–15:2)( ignoring that the standard to be
`
`applied is a "person of ordinary skill in the art," not an expert). For this
`
`1.
`
`

`

`
`
`proposition, PO's counsel cites to an isolated statement by Akhlaghi presented in a
`
`misleading way, because PO deleted reference to the word "only" (Ex. 2011 at
`
`24:5-9), as well as omitted to mention that Akhlaghi testified immediately prior to
`
`her supposed admission (above) that while her CV didn't list formulation
`
`development, she is the Ernest Mario Distinguished Chair of Pharmaceutics
`
`(Pharmaceutics, of course, being the science of dosage form design, i.e.,
`
`formulation), has four-(4) formulator faculty members in her group plus graduate
`
`students in pharmaceutics, she is a pharmacist /doctor of pharmacy with "very
`
`good familiarity with formulation," (Ex. 2011 at 23:19–24:4), that she testified a
`
`few minutes later that "I am an expert" (in formulation) (Ex. 2011 at 24:14).
`
`As to PO's argument that Akhlaghi's testimony should be given minimal or
`
`no weight because it is "confusing", any confusion stems not from any lack of
`
`expertise on Akhlaghi's part, but rather solely from PO counsel's own purposeful
`
`facile sleight of hand in framing his deposition questions between the ever
`
`changing transposition of the phrases "mean Tmax" (Ex. 2011 at 70:5 -9; 70:8 –
`
`71:21, 72:21), "arithmetic mean Tmax" (Ex. 2011 at 73:2-3), "single mean Tmax"
`
`(Ex. 2011 at 78:17), and Tmax (Ex. 2011 at 65:9; 66:11; 67:8; 71:12), including
`
`frequently conflating these phrases (See, Ex. 2011 at 66:11-14:
`
`So when you're assessing a Tmax, a mean Tmax from a
`population of patients, there's really no expectation of
`where that might fall in terms of the type of
`distribution?" (emphasis added) ("So what is the single
`
`2.
`
`

`

`
`
`
`mean Tmax value you calculated form the data presented
`in Timmins? ... And you'd agree that a mean Tmax is a
`single number that's calculated from a population of
`patients?" (Ex. 2011 at 73:8 – 22); "And a mean Tmax –
`pardon a arithmetic mean Tmax." (Ex. 2011 at 73:2-3)(
`emphasis added)
`
`To the extent any answers were confusing, it was a result of PO's counsel's
`
`posing his repetitive questions in a purposefully confusing manner. For instance,
`
`PO's counsel refused to clarify what he meant by phrases such as "single mean
`
`Tmax" value, even after Akhlaghi cautioned him that "[a] single arithmetic mean
`
`Tmax in any case in science … does not mean anything without the standard
`
`deviation about it." (Ex. 2011 at 74:6-11).
`
`Along the same lines, PO argues that "Akhlaghi was unable to provide clear
`
`and consistent testimony regarding the purported disclosure of a mean Tmax value
`
`in Timmins" (Paper 25, 15:3-4), which is premised on adding another Tmax phrase
`
`into its lexicon "single 'true' mean Tmax" (emphasis added) (Paper 25, 2:1-2). PO's
`
`counsel thus creates a misimpression because this phrase was never used at all
`
`during Akhlaghi's deposition. Out of context, PO's counsel misquotes Akhlaghi as
`
`having testified "everybody is guessing here"(Paper 25) to falsely imply that
`
`Akhlaghi indicated that one could not determine by the newly introduced phrase
`
`that "single 'true' mean Tmax value."
`
`3.
`
`

`

`
`
`
`When confused and disjointed questions did not sow what counsel for PO
`
`wanted to harvest, PO's counsel reverted to mischaracterization. 1 For examples,
`
`PO's counsel states "despite inconsistent and confused testimony from Petitioner's
`
`declarant, her most credible, non-conclusory testimony shows that a POSA would
`
`understand that the mean Tmax value of Timmins would be based on a normal
`
`distribution of individual patient Tmax values and would thus likely fall below the
`
`claimed ranges." (Paper 25, 8-12). However, Akhlaghi actually testified "Tmax is a
`
`discrete variable. A discrete variable is not subject to normal distribution."
`
`(emphasis added) (Ex. 2011 at 64: 21-22).
`
`Indeed, it is telling that PO's expert witness (Dressman's declaration)
`
`includes as an exhibit a webpage from Certara.com (Ex. 2006), but without any
`
`corresponding discussion of the same in her declaration. Nonetheless, the Certara
`
`webpage actually supports Akhlaghi's statement without respect to Tmax not being
`
`subject to a normal distribution (Ex. 2011 at 64:21–65:32): "Tmax is a discrete
`
`variable. A discrete variable is not subject to normal distribution very well. That's
`
`why reporting median, we always – FDA guidelines actually suggests, reporting
`
`median for Tmax values"). In that it states: "when you summarize Tmax results, you
`
`
`If there is any confusion it relates to PO's actions, not the Petitioner. In the concurrent
`1
`litigation plaintiffs have asserted claim 1 in identical form as set forth in the IPR even though in
`2012 in Sciele Pharma v. Lupin Ltd, 684 F.3d 1253 (Fed. Cir. 2012)("Sciele"), the same plaintiffs
`admitted in a pointed exchange with Judge Moore (See Audio Recording 2012-1228(2) 13:22–
`16:18), that it was asserting a claim the USPTO had rejected as obvious in light of the prior art.
`
`4.
`
`

`

`should NOT use averages and standard deviation, as they do not accurately
`
`describe the distribution of values. Instead, you should use medians and ranges
`
`
`
`
`…"(Id.)
`
`II. The Prior Art
`
`
`
`
`
`Cheng et al. WO 99/047125 (Ex. 1002)
`
`PO does not dispute that Cheng WO 99/047125 ("Cheng") is prior art.
`
`Cheng discloses a controlled release anti-hyperglycemic tablet that does not
`
`contain an expanding polymer (as in the case of GLUCOPHAGE® XR) and
`
`comprises a core containing an anti-hyperglycemic drug, a semipermeable
`
`membrane coating the core and at least one passageway in the membrane
`
`(Abstract).
`
`As noted in Akhlaghi's Declaration concerning the invalidity of all of the
`
`claims of the '866 patent, Cheng discloses the same tablet structure claimed in the
`
`'866 patent (Ex. 1019 at ¶145-146), and has essentially the same type and amounts
`
`of excipients in its composition. (Ex. 1019 at ¶149). To the extent there is any
`
`difference Akhlaghi notes that the formulation of the '866 patent includes another
`
`passageway, that is laser-drilled hole (Ex. 1019 at ¶153). Although the device of
`
`Cheng is stated in the '866 patent to provide a Tmax of 8-12 hours under all
`
`conditions of feeding,2, a Tmax range of 4-10 hours is actually demonstrated (Ex.
`
`
`2 Id., p. 3, lines 14-17.
`
`5.
`
`

`

`
`
`1019 at ¶151 – pointing to Figures 4-8) The claims of the '866 patent assert a Tmax
`
`of 5.5-7.5 hours in vivo when administered after dinner.
`
`Akhlaghi points out that it would be trivial for a POSA to increase the rate
`
`of release of metformin from the tablet of Example 3 of Cheng to match Tmax
`
`values in vivo as seen in Timmins by drilling another laser hole (Ex. 1019 at
`
`¶155). Indeed, the inventors admitted directly to the Examiner during prosecution
`
`of the '866 patent that a POSA would easily alter the controlled release
`
`formulations of the prior art to produce the in vivo Tmax range specified in the '866
`
`patent:
`
`In addition, at the time the application was filed,
`numerous controlled release technologies were well
`within the knowledge of pharmaceutical formulators
`having ordinary skill in the art. Such pharmaceutical
`formulators know that controlled release technologies
`can be manipulated to provide a formulation which
`upon in-vivo testing will provide the Tmax range of the
`present invention. This fact is supported, e.g., by a
`simple review of patents discussed in the specification
`concerning formulation technologies, which patents
`provide ranges of ingredients. These ranges represent
`the acknowledgement of those skilled in the art that a
`certain amount of experimentation is considered to be
`necessary
`to manipulate a
`controlled
`release
`technology to obtain a desired release pattern of the
`drug.3 [Emphasis added]
`
`
`
`3
`File history of U.S. Patent No. 6,866,866 (EX1010), Amendment under 37
`C.F.R. 1.111, February 24, 2003, p. 8-p. 9.
`
`
`6.
`
`

`

`
`
`
`See also '866 patent, col 12, lines 42-46.
`
`
`
`Timmins et al. WO 99/47128 (Ex. 1003)
`
`PO does not dispute that Timmins et al., WO 99/47128 is prior art.
`
`Timmins teaches among embodiments a biphasic controlled release delivery
`
`system for metformin HCL salt comprising an inner solid particulate phase with
`
`one or more hydrophilic polymers, and hydrophobic material, and another solid
`
`continuous phase in which the granules are embedded and dispersed throughout.
`
`(Ex. 1019 at ¶159). This device differs functionally from the device of the '866
`
`patent which is an osmotically driven tablet, which function by allowing gastric
`
`or intestinal fluid to permeate into the osmotically active core, dissolving the
`
`active agent, and expelling it through the surrounding impermeable membrane
`
`through the passageways in the membrane.(Ex. 10019 at ¶187).
`
`Timmins' disclosure covers Bristol-Myers Squibb's product,
`
`GLUCOPHAGE® XR, which was approved for marketing (October 13, 2000)
`
`before the priority date of the '866 patent. Timmins teaches a Tmax range of 4-8
`
`hours, with a median (not mean) Tmax of 5 hours for a single dose after dinner
`
`administration.4 (Ex. 1019 at ¶160). Being a competitor's product to their own
`
`extended release metformin product ("metformin XT" in the '866 patent, now
`
`"Fortamet"), the inventors would have been well aware of that. (Ex. 1019 at ¶160).
`
`
`4 WO 99/47128, p. 34, lines 28-29.
`
`7.
`
`

`

`
`
`III. The POSA Would be Motivated to Target a Mean Tmax Range of the
`Claims In a Formulation of Cheng Based on Timmins
`
`PO tries to make much out of the fact that the two-(2) references Petitioner
`
`relies upon "were before the PTO during the prosecution of the '866 patent." (Paper
`
`25, 7:4-6). However, PO makes no mention that in Sciele v. Lupin 684 F.3d 1253
`
`(Fed. Cir. 2012)("Sciele") the Federal Circuit dispensed with this argument noting
`
`that the law only provides that new evidence may carry more weight. Overall, it
`
`specifically found the two references "considered in light of the prosecution history
`
`and the correct standard of proof raise a substantial question of invalidity." Id. at
`
`1261.
`
`
`
`As determined in Sciele, and supported by Akhlaghi's analysis set forth in
`
`the claim charts to her declaration in support of the Petition (Ex. 1019, ¶¶196-197),
`
`a POSA would understand that Cheng "discloses all of the limitations of the
`
`asserted claims except for the Tmax range of 5.5 to 7.5 (Cheng discloses a Tmax of 8
`
`to 12 hours)" (Sciele at 1261)
`
`The confusion sowed by PO's counsel using multiple constructs/variations of
`
`Tmax and mean Tmax, along with mischaracterizing Akhlaghi's testimony on the
`
`distribution of expected with Tmax values (which PO's counsel wanted her to say
`
`was a normal distribution) was entirely calculated to support the completely
`
`unsupportable argument made in PO's Response at pages 27–39.
`
`8.
`
`

`

`
`
`
`PO argues that Timmins, while possible suggesting a dosage form with
`
`extended release in the upper GI tract, would not lead one to a particular mean Tmax
`
`value or range of mean Tmax values, such as specified in claims 2, 3, 23 and 24
`
`(Paper 25 at 27). PO's counsel misrepresents Ahklaghi's testimony to suggest the
`
`Tmax values follow normal distribution, in an obvious attempt to prop up Dressman,
`
`who had already posited an argument related to a normal distribution of Tmax would
`
`argue against the Tmax range asserted in the claims, in that in a normal distribution
`
`one would expect the Tmax of only a few patients at the lower and higher extremes
`
`of the ranges. (Ex. 2010 at ¶10). Clearly, this ignores the fact that patentability is
`
`not found in merely specifying a broader range about an obvious desired range.
`
`PO's non-sequitur argument that a normal distribution means that the "likely
`
`distribution of individual Tmax values from Timmins produces a mean Tmax below
`
`the claimed ranges," falls on its own, as Akhlaghi did not agree that Tmax is a
`
`parameter that is associated with a normal distribution.
`
`Dressman further falsely states that Akhlaghi admitted in her deposition that
`
`"mean Tmax is a single value, not a range of valves" (emphasis in original;
`
`Dressman Decl. at 27:5-6), which Akhlaghi clearly did not.5 (see Ex. 2011 at 74:6-
`
`
`Indeed, this statement makes complete sense given Akhlaghi's assertion that
`5
`the mean Tmax would range from 4.67 to 6.33 hours (Ex. 2011 at 77:20) with a
`standard deviation about a single arithmetic mean Tmax (Ex. 2011 at 74:9-11) (the
`latter assertion by Akhlaghi is supported by tables 1, 3 5 and 6 of the '866 patent
`
`9.
`
`

`

`
`
`
`11; Ex. 2011 at 74:10-11: "'mean Tmax is meaningless without the standard
`
`deviation around it.")
`
`PO asserts that Timmins "provides insufficient information for such a person
`
`to determine the mean Tmax of Timmins" (Paper 25, at 2:18-19). PO also argues
`
`that a POSA would not target a mean Tmax based on Timmins, absent the benefit of
`
`hindsight (Paper 25, 17:16-17) because: (1) "a mean Tmax value is nowhere
`
`disclosed by Timmins" (Paper 25, 18:12), and (2) because Timmins would not
`
`teach "that any particular mean Tmax or ranges of mean Tmax values would be
`
`desirable for a dosage form of metformin" (Paper 25, 18:18-19). However, albeit
`
`many of the same attorneys were on the case, PO's counsel completely ignores the
`
`Federal Circuit's ruling in Sciele, which is directly counter to these formerly raised
`
`positions.
`
`As concerns reaching of a range of mean Tmax values in regard to Timmins,
`
`the panel in the Sciele case remarked that "[a]lthough Timmins expressly discloses
`
`a median Tmax, it also provides the raw data from which one skilled in the art could
`
`compute the range of possible mean Tmax values. J.A. 2501-02.2 Based on this data,
`
`one skilled in the art would understand that the mean Tmax in Timmins must fall
`
`between 4.67 and 6.33 hours, " (Sciele. at 14), the same range that Akhlaghi's
`
`
`each of which show a different mean Tmax value with a value of standard deviation
`of 1 or 2 hours in parenthesis).
`
`
`10.
`
`

`

`calculations led her (that is, 4.67 to 6.33 hours -- Ex. 2011 at 77:20). Indeed, one of
`
`the Federal Circuit panelists at the oral hearing (believed to be Judge Moore) walked
`
`
`
`
`through how a POSA would determine the same:
`
`We know (referencing Timmins) … that the result
`presented in the table are 24 patients to whom this was
`administered immediately after dinner. We also know
`the median was 5 with a lower limit of 4 and an upper
`limit of 8. OK. Do you know it's mathematically
`impossible for that to result in a mean higher than 6.33?"
`… that 98% of the 24 different patients, and the numbers
`that could fit into it, are right in the claimed range. In
`only a couple of them does it fall below the claimed
`range. …The whole issue following Cheng and the
`Examiner was nothing discloses below 8. So if you had
`something that discloses 4.67 and something that
`discloses 8, why isn't the range of 5.5 to 7 obvious in
`light of these two disclosures?
`
`Sciele Oral Argument 2012-1228.mp3 at 19.36–21.29 available at
`
`http://www.cafc.uscourts.gov/oral-agrument-recordings/2012-2018/all .
`
`PO and its affiliates were all parties in Sciele, (Sciele subsequently changed
`
`its name to Shionogi Pharma, Inc. - "Shionogi").
`
`The Federal Circuit's stated in Sciele that a POSA would understand that:
`
`[T]immins…describes a controlled release formulation of
`metformin and explains that its formulation releases
`metformin in the portion of the gastrointestinal tract
`where better absorption of the drug can occur… The
`earlier release of the drug increases bioavailability and
`leads to a lower Tmax."
`
`Id. at 1261.
`
`11.
`
`

`

`
`
`
`Timmins explains that 'improved bioavailability from an
`extended release dosage form that releases metformin at
`a rate likely to provide the desired plasma levels of drug
`for an extended period [could result] from a dosage form
`that has extended residence time in the upper
`gastrointestinal tract … In other words, that earlier
`release, resulting in a lower Tmax, provides the benefit of
`'the desired plasma levels of drug for an extended time
`period.
`
`Id. at 1255. Akhlaghi agrees with the Federal Circuit's conclusion. (Ex. 1019 at
`
`¶75).
`
`PO's protestation that a "a POSA would not have been motivated to combine
`
`Cheng and Timmins" makes no mention that Akhlaghi's contrary position was also
`
`held by the Federal Circuit panel in Sciele:
`
`Timmins thus teaches one skilled in the art to lower the
`Tmax of Cheng (8 hours)," Id.at 1261, because of the
`benefits Timmins indicates comes along with the lowered
`Tmax (e.g., improved drug release in vivo - Timmins WO
`99/47128 at 34; and the teaching that "earlier release,
`resulting in a lower Tmax, provides the benefit of the
`desired plasma levels of drug for an extended time period
`.. reduction in dosing frequency … improve[d]
`compliance as well as an extended time period over
`which therapeutically beneficial plasma levels of drug
`[are] maintained"
`
`Sciele. 648 F.2d at 1256.
`
`
`Akhlaghi also fully agrees with the Federal Circuit's following reasoning in
`
`Sciele, which would lead the POSA to match the mean Tmax range of Timmins:
`
`Timmins also identifies a number of benefits stemming
`from an earlier extend release, including 'reduction in
`
`12.
`
`

`

`
`
`
`dosing frequency, providing patient convenience that
`would probably improve compliance as well as an
`extended time period over which therapeutically
`beneficial plasma levels of drug were maintained.
`
`Id. at 1255; accord Akhlaghi Declaration, Claim 1 of Claim Chart, Ex. 1019, ¶¶
`
`196-197, pp. 70- 81.
`
`PO's assertion that Timmins, would not teach "that any particular mean Tmax
`
`or ranges of mean Tmax values would be desirable for a dosage form of metformin"
`
`to provide a motivation to alter the formulation of Cheng (Paper 25 18:18-19) is
`
`also belied by Sciele as follows:
`
`In other words, that earlier release, resulting in a lower
`Tmax, provides the benefit of “the desired plasma levels of
`drug for an extended time period.” Id. Timmins also
`identifies a number of benefits stemming from an earlier
`extended release, including “reduction in dosing
`frequency, providing patient convenience that would
`probably improve compliance” as well as “an extended
`time period over which therapeutically beneficial plasma
`levels of drug were maintained.” Id. These benefits
`would motivate one skilled in the art to modify Cheng to
`achieve a lower Tmax range. Cf. KSR, 550 U.S. at 424.
`
`Id. At 1255-1256.
`
`
`
`As Akhlaghi identified, applicants noted in an amendment under 37 C.F.R.
`
`§1.111 of February 24, 2003 in the Prosecution File History of Application Serial
`
`No. 09/705,630 (p. 7) (Ex. 1010) that "once the Tmax range which provides for a
`
`useful dosage form has been established, other controlled release technologies
`
`known in the art can be manipulated and tested to achieve this Tmax range without
`
`13.
`
`

`

`
`
`
`undo experimentation." (See Akhlaghi Declaration, Claim 1 of Claim Chart, Ex.
`
`1019, ¶¶196-197, pp. 70-81). Timmins, having defined a Tmax range which
`
`provided special benefit, means that the artisan would have no problem matching
`
`this Tmax range.
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`IV. There is No Teaching Away from Combining Cheng and Timmins
`
`
`
`PO argues that "[a] POSA would not have combined Timmins and Cheng
`
`because they are directed to different mutually exclusive dosage forms" (Paper 25,
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`21:5-6), and because Cheng teaches away from the combination with Timmins in
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`"emphasiz[ing] that the once-a-day administration of metformin and the improved
`
`bioavailability profile are contingent upon the dosage form having its peak plasma
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`level between 8-12 hours after administration" (Id. at 22:3-10) which they assert
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`would drive away a POSA from Timmins in "render[ing] Cheng unsatisfactory for
`
`its intended purpose of providing a formulation having a mean Tmax value of 8 to
`
`12 hours." (Id. at 22:18-20)(emphasis in original)
`
`
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`First, it is indisputable that if a given course of action has both simultaneous
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`advantages and disadvantages, this does not obviate the motivation to combine.
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`See Medichem S.A. v. Rolabo S.I., 437 F.3d 1157, 1165 (Fed. Cir. 2006). Second,
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`there is nothing in Cheng that directly teaches (as PO incorrectly asserts -- Paper
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`25, 22:7-10) that any improvements seen in bioavailability are strictly limited to
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`having a peak plasma level only between 8–12 hours after administration. Indeed,
`
`14.
`
`

`

`
`
`
`one section of Cheng that PO cites to support this argument is actually limited to a
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`"preferred embodiment" (4:3-4) and does not link the improvements in
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`bioavailability noted in the patent to the specific Tmax range of 8-12 hours as PO
`
`asserts. As noted by the Federal Circuit in Meiresonne v. Google, Inc., Case No.
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`16-7855 (Fed. Cir, March 2017) when a reference "merely expresses a general
`
`preference for an alternative invention but not criticize, discredit, or otherwise
`
`discourage investigation into" other embodiments, the reference does not teach
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`away. Id. at 1382.
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`Indeed, as this Board has noted concerning teaching away, "there is no
`
`requirement that in determining obviousness, every goal or objective of a prior art
`
`reference must be advanced when relying on any technical disclosure of the
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`reference." Garmin Int'l Inc. v. Cuozzo Speed Tech. Inc. IPR2012-0001
`
`(November 13, 2013) (non-precedential) (finding no "teaching away" to overcome
`
`an obviousness rejection unless a proposed combination "cannot be accomplished"
`
`or "cannot work.").
`
`
`
`Whether Akhlaghi thought "the dosage form of Timmins was more desirable
`
`than Cheng, and that Cheng was not an advance over Timmins," is irrelevant as to
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`whether a POSA would combine the two references opined to by both Akhlaghi
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`and the Federal Circuit in Sciele.
`
`15.
`
`

`

`
`
`V. A POSA Would Have A Reasonable Expectation of Success in Combining
`Cheng and Timmins
`
`To establish a prima facie case of obviousness, there must be a reasonable
`
`expectation of success. See, e.g., PharmaStem Therapeutics, Inc. v. ViaCell, Inc.,
`
`491 F.3d 1342, 1360 (Fed. Cir. 2007) (citing KSR, 550 U.S. at 417). This
`
`expectation, however, need not be guaranteed or amount to absolute predictability.
`
`In re O'Farrell, 853 F.2d 894, 903-904 (Fed. Cir. 1988) (citation omitted). As
`
`noted by the Supreme Court in KSR Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007)
`
`simple substitution of known elements for another, or use of known techniques to
`
`improve a method in a similar way, such that the substitution or techniques are
`
`"obvious to try" to one of ordinary skill, may form the basis of establishing
`
`obviousness.
`
`PO urges that the Board should ignore in the panel's analysis concerning
`
`whether there was an expectation of success in combining Cheng and Timmins,
`
`PO's previous admission that "pharmaceutical formulators know that controlled
`
`release technologies can be manipulated … to provide a formulation which upon
`
`in-vivo testing will provide the Tmax range of the present invention:" made during
`
`prosecution, because it was made in respect of an enablement rejection. (Paper 25,
`
`24:3-7). PO omits to mention, however, that PO propounded, and lost, a near
`
`identical argument before the Federal Circuit in Sciele concerning a parallel
`
`statement it made in the prosecution history of the application leading to the '866
`
`16.
`
`

`

`
`
`
`patent, viz., "that one skilled in the art would be able to manipulate the process and
`
`formulations of the [prior art] by other methods to obtain the claimed
`
`pharmacokinetic parameters of the present invention by routine experimentation."
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`With respect to the latter statement, the Federal Circuit in Sciele reasoned,
`
`(and with which Akhlagi agrees):
`
`[W]e are hard pressed to understand this distinction.
`Coupled with the motivation to lower Tmax, as disclosed in
`Timmins, the applicant's characterization of predictability
`and skill in the art during prosecution provides evidence
`that it would have been routine and obvious design choice
`to make an extended release dosage form with a lower
`Tmax.
`
` Sciele at 1263; accord Akhlaghi Declaration, Ex. 1019, Claim Charts, ¶¶196-197).
`
`Lastly, PO relies on Dressman's Declaration (Ex. 2010) for the proposition
`
`that "a POSA would not have reasonably expected to combine the teachings from
`
`… Cheng … and Timmins .. to achieve the target mean Tmax range of 5.5 – 7.5
`
`hours of the '866 patent without undue experimentation." (Paper 25, 24:18 –
`
`25:3)(emphasis added). Dressman did not say this, however, instead asserting that
`
`"a POSA could not predict in advance whether a second laser-drilled hole in the
`
`dosage form of Cheng would produce an adequate reduction of mean Tmax into the
`
`range claimed in the '866 patent on the one hand or overshoot the desired rate of
`
`release on the other hand." (Ex. 2010 at ¶67).
`
`17.
`
`

`

`
`
`
`The fact that some experimentation might be undertaken as suggested by
`
`Dressman