Paper No. 14
` Paper Filed: October 3, 2016
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`
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________
`
`INTELGENX CORP.
`Petitioner,
`
`v.
`
`ICOS CORP,
`Patent Owner.
`
`
`
`
`
`
`Case No. IPR2016-00678
`Patent 6,943,166
`
`REQUEST FOR REHEARING UNDER 37 C.F.R. §42.71
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` Paper Filed: October 3, 2016
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`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________
`
`INTELGENX CORP.
`Petitioner,
`
`v.
`
`ICOS CORP,
`Patent Owner.
`
`
`
`
`
`
`Case No. IPR2016-00678
`Patent 6,943,166
`
`REQUEST FOR REHEARING UNDER 37 C.F.R. §42.71
`
`
`
`
`
`
`
`
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`
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`
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`In the Decision issued September 1, 2016, the Board declined to institute the
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`above-captioned Inter Partes Review challenging claims 1-12 of U.S. Patent No.
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`6,943,166 (“the ‘166 Patent”). Specifically, the Board found that Petitioner did
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`“not point to the asserted prior art or otherwise explain why an ordinary artisan
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`would limit the tadalafil dose to 20 mg per day.” Decision, Paper 13 at 7.
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`Petitioner believes the Board overlooked or misapprehended the Petitioner’s
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`arguments on this point and thus requests rehearing.
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`I.
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`LEGAL STANDARD
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`Under 37 C.F.R.§42.71(d), a party requesting rehearing of a decision must
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`(1) identify all matters the party believes the Board misapprehended or overlooked,
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`and (2) the place where each matter was previously address in a motion, an
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`opposition, or reply. The Board reviews the decision for an abuse of discretion. 37
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`C.F.R. §42.71(c).
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`A request for rehearing of a denial to institute inter partes review is
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`appropriately granted where the Board has misapprehended the significance of the
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`prior art cited by the Petitioner, or the significance of Petitioner’s arguments
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`regarding prior art. See Merial Ltd. v. Virbac, IPR2014-01279, Paper 18 at 1, 7
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`(rehearing granted where the Board overlooked the significance of disclosures in
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`the prior art); Handi Quilter, Inc. v. Tacony Corp., IPR2014-00270, Paper 17 at 24
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`(rehearing granted where the Board overlooked the significance of Petitioner’s
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`
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`prior art arguments). The Patent Owner’s retained ability to prove the Petitioner
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`wrong after inter partes review favors rehearing. See Merial, IPR2014-01279,
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`Paper 18 at 12; Handi Quilter, IPR2014-00270, Paper 17 at 24.
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`II. ARGUMENT
`In its Decision, the Board agreed with the Petitioner that Daugan (Exh.
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`1002) teaches the composition of tadalafil, and its use for treating male or female
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`sexual dysfunction. Decision, Paper 13 at 4. The Board also agreed that Daugan
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`teaches a dose range of 0.2-400 mg of active compound, with a specific example of
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`50 mg, where the dose can be administered once per day, or multiple times per
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`day. Id. at 4-5. The Board also agreed that the SNDA (Exh. 1003) teaches that (1)
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`sildenafil (a/k/a Viagra®), like tadalafil, is a potent PDE5 inhibitor for treating
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`erectile dysfunction, (2) sildenafil is therapeutically effective at doses of 25, 50,
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`and 100 mg, and (3) sildenafil can also be therapeutically effective at doses as low
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`as 5 and 10 mg in some patients. Id. The Board also agreed that the SNDA’s
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`maximum dosing recommendation is once per day. Id. at 5.
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`The Board recognized Petitioner’s overarching argument that, “because
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`tadalafil is a more potent and highly selective PDE5 inhibitor, an ordinary artisan
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`would have had a reason to use doses lower than the 50 mg dose exemplified in
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`Daugan including doses lower than the known effective doses of sildenafil, and
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`would have had a reasonable expectation of success in doing so.” Id. at 6 (citing
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`2
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`
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`Petition, Paper 1, at 26-28, 42-44). However, the Board did not institute the
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`proceeding. Instead, the Board agreed with the Patent Owner’s contention that the
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`Petition “fail[ed] to account for another essential claim limitation – ‘a maximum
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`total dose of 20 mg per day.’” Id. (citing Preliminary Response, Paper 11, at 13-
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`22). The Board concluded that “Petitioner appears to ignore the maximum-total
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`dose requirement. Petitioner’s analysis reflects this omission.” Id.
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`Petitioner submits that the Board was incorrect on this point, because
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`Petitioner did not ignore the maximum-total dose requirement. Particularly,
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`Petitioner submits that the Board overlooked specific instances where the Petition
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`identified and explained how the 20 mg per day maximum claim limitation is
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`obvious over prior art. The most specific of these teachings was cited in Ground 2,
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`i.e., the obviousness combination of Daugan (Exh. 1002) and the SNDA (Exh.
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`1003), which is the focus of the Petitioner’s request for rehearing.
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`A.
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`The Board Overlooked or Misapprehended the Petitioner’s Citations
`to the Maximum Dose Requirement
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`The Petitioner included a significant number of exhibits in its Petition, and
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`in Ground 2 relied predominantly on the SNDA (Exh. 1003) relating to sildenafil,
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`coupled with the acknowledged higher potency for tadalafil, as teaching the 20 mg
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`per day maximum dosage for tadalafil. Specifically, the Petitioner cited the SNDA
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`as teaching therapeutically effective once per day dosages of sildenafil that were
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`near and less than 20 mg, including 25 mg doses and doses as low as 5 and 10 mg.
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`3
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`Petition at 41-44. Petitioner then explained how that would suggest to a person of
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`ordinary skill in the art to use a lower dose amount of tadalafil due to its known
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`higher potency. Id. Because the doses in the SNDA were once per day, i.e.,
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`“single,” Petition at 41, a lower unit dose of tadalafil would necessarily be a lower
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`maximum per day, thus accounting for both aspects of the last clause of Claim 1.
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`Additionally, as set forth in detail in the Petition, a person of ordinary skill
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`would have sought to identify the lowest dose of a drug that still provides the
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`maximum therapeutic efficacy by, among other things, generating dose response
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`curves to identify the maximum dose range. Petition at 12-14.
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`1.
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`The SNDA (Exh. 1003) Teaches Therapeutically Effective
`Single Daily Doses of Tadalafil Near and Below the Maximum
`20 mg Per Day Limitation in Claim 1
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`The sildenafil dosing regimen studies cited by Petitioner were conducted
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`with a single dose given once per day. Hence, the amount of that single dose was
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`also the maximum total dose per day, as claimed in the ‘166 Patent. The Petition
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`offered a number of citations to maximum doses of sildenafil near or under 20 mg
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`given once per day.
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`For example, in the claim chart for Ground 2 Petitioner quoted the SNDA as
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`stating “The study consisted of two parts. In the first part, subjects received, in
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`random order, single doses of placebo and sildenafil 10, 25, and 50 mg on
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`separate study days 3 days apart.” Petition at 41 (citing Exh. 1003 at
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`4
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`215)(emphasis in original). This quotation was included in the claim chart for
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`Ground 2 directly adjacent the 20 mg per day maximum limitation set forth in
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`Claim 1.
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`A “single dose” per day of 10 mg – exactly as emphasized in bold in the
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`claim chart – is not just a unit dose of 10 mg. It is also a maximum total dose of 10
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`mg per day, because it is given only once per day. This point is made clear by the
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`SNDA because in the very same sentence the SNDA indicates that the “single”
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`dose is delivered on “separate study days 3 days apart.” Id (emphasis added). That
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`clearly means the SNDA study teaches just one dose per day at defined amounts,
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`including an amount that is less than the 20 mg maximum per day dose claimed in
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`the ‘166 Patent.
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`Page 215 of the SNDA cited in the Ground 2 claim chart confirms the study
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`was directed to the efficacy of single daily doses, also using the term “per day” in
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`reference to the amount tested. Exh. 1003 at 215. The same is true of the SNDA’s
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`page 126 (studying doses as low as 5 mg taken “not more than once per day”) and
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`page 152 (studying “single doses” that were “separated by at least 7 days”), both of
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`which were cited in the Ground 2 claim chart. Id. at 126, 152; Petition at 40-41.
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`Petitioner introduced this point earlier in the State of the Art section of the
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`Petition. Specifically, Petitioner pointed out that “VIAGRA®’s product label from
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`1998 states that the ‘maximum daily dosing frequency is once per day.’” Petition
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`5
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`
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`at 7 (citing Exh. 1016 at 17 and Exh. 1003 at 50). Petitioner further pointed out
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`that sildenafil was therapeutically effective in doses as low as 5-10 mg. Petition at
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`7-8 (citing Exh. 1003 at 127-128, 215, 217-2191 and Exh. 1009 at 51). Petitioner
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`cited the same pages from the SNDA -- 127-128, 215, and 217-219 -- as showing
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`therapeutic effectiveness for single sildenafil doses near or below 20 mg. Petition
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`at 8. Like pages 127-128 and 215, which were also cited in the Ground 2 claim
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`chart as studies on dosages given once per day, pages 217-219 also disclosed a
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`study showing therapeutic effectiveness of 10 mg doses taken “once per day.”
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`Exh. 1003 at 217. All these citations were also included specifically in the Section
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`for Ground 2 as well. Petition at 39, 42, and 44.
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`Similarly, Exh. 1009, and particularly pages 49-52 thereof, was cited in both
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`the State of the Art and Ground 2 sections of the Petition. Petition at 7, 8 and 39.
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`That evidence was cited for the exact same proposition that sildenafil is
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`therapeutically effective at doses near or below 20 mg (including 10 and 25 mg).
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`Exh. 1009 at 49. Again, like the other studies cited by Petitioner, Exh. 1009’s
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`study was for a “single dose” given days apart, namely “at least three days.” Id.
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`Hence, the “single dose” amount was also the maximum per day dosage amount.
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`1 Notably, pages 127-128 of the SNDA (Exh. 1003) describe the results for the
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`doses given once daily cited in the Ground 2 claim chart.
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`6
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`Because the cited studies, including specifically those cited in Ground 2,
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`showed therapeutic efficacy for sildenafil doses as low as 10 mg – or even 5 mg –
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`given once per day, and those values are less than 20 mg, they addressed the 20 mg
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`per day maximum claim limitation. The citation to and emphasis on the “single
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`dose” of 10 mg on “separate study days” in the Ground 2 claim chart (Petition at
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`41) was included not just because it addressed the unit dosages (1-20 mg), but also
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`because a “single dose” per day satisfied the maximum per day claimed in the ‘166
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`Patent.
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`That is the only logical interpretation when the word “single” is used to
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`identify the number of doses given on each of the “separate study days,” Petition at
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`41, and the sole reason why Petitioner emphasized the word “single” in the Ground
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`2 claim chart adjacent to the maximum dose per day limitation. Indeed, the
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`emphasized word “single” has no significance other than with respect to the
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`maximum per day limitation -- it denotes that just one dose is given per day, thus
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`meaning the unit dose itself is also the daily maximum. The same is true of all the
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`other evidentiary citations in the Petition noted herein that point to single daily
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`doses taught by the prior art.
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`7
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`2.
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`The SNDA (Exh. 1003) Single Daily Dose Studies Would
`Suggest Doing the Same With Tadalafil, but in Smaller
`Amounts Due to Tadalafil’s Known Higher Potency
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`The Board correctly noted Petitioner’s point that tadalafil is more potent
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`than sildenafil. Decision, Paper 13 at 5. Thus, there seems be no dispute that this
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`fact would give one of ordinary skill in the art a reason to use a tadalafil dosage
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`that is smaller than the therapeutically effective single doses of sildenafil near or
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`under 20 mg taught in the SNDA. Exh. 1005 at ¶¶117-122 (e.g., at ¶120 “A POSA
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`using the SNDA as a guide would have had a reason to try similar or even lower
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`amounts of tadalafil, because tadalafil selectively inhibits the same enzyme target
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`as sildenafil and is a more potent PDE-5 inhibitor.”).2
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`However, the Board misunderstood Petitioner as only relying on the SNDA
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`to teach a unit dose range for sildenafil as a starting point that, in turn, would
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`suggest a lower unit dose range for tadalafil (claimed as “about 1 to about 20 mg”)
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`due to its higher potency. Decision at 6. By doing so, the Board misapprehended
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`or overlooked Petitioner’s argument. While the Petitioner did rely on the SNDA
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`2 Several of these paragraphs in the Declaration of Wayne J.G. Hellstrom’s, M.D.,
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`FACS (Exh. 1005) were cited in the Petition, for example in the Ground 2
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`section at pages 39, 41-44.
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`8
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`for the unit dose point, the Petitioner also relied on the SNDA for the maximum
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`daily dosage claim limitation. Supra Section II.A.1.
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`Once it is understood that the SNDA’s therapeutically effective single doses
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`of sildenafil near or under 20 mg, including doses such as 5, 10 and 25 mg, are
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`each both the unit dose and the maximum total dose per day, the significance of
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`Petitioner’s argument is clear. The Petitioner argued that a person of ordinary skill
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`in the art, with knowledge of the therapeutic effectiveness of a single daily dose of
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`sildenafil from the SNDA, would have used a lower dose of tadalafil below 20 mg
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`due to its higher potency. Petition at 3 (referring to the studies in Exh. 1003 -
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`“Because tadalafil showed greater potency than sildenafil under industry-accepted
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`in vitro studies, a POSA would have been motivated to use a similar dosing
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`regimen for tadalafil as had already been shown to be effective with
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`sildenafil.”)(citing Exh. 1005 at ¶75-79) (emphasis added); see also Petition at 39,
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`41-44; Exh. 1005 at ¶¶117-122. Because the Petitioner argued that the SNDA’s
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`once a day dose that “had already been shown to be effective with sildenafil”
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`would have disclosed or rendered obvious administering a lower once a day dose
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`of tadalafil, Petitioner addressed both the unit dose and the maximum daily total
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`limitations of Claim 1 of the ‘166 Patent. A single unit dose administered daily, as
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`taught by the SNDA, is the same thing as a maximum daily total. Petition at 3, 39,
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`41-44; Exh. 1005 at ¶¶75-79, 117-122.
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`9
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`3.
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`The Patent Owner’s Preliminary Response Mis-Framed The
`Issue, and Likely Led to the Board’s Mistake
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`In its Preliminary Response, the Patent Owner incorrectly faulted the
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`Petitioner for not making “separate” arguments or addressing the unit dose and
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`daily maximum as “separate” limitations. Preliminary Response, Paper 11, at 13
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`and 15-17. The Board was incorrectly persuaded by Patent Owner’s argument on
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`this point. Decision at 6 (citing Preliminary Response, Paper 11, at 13-22).
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`The Patent Owner’s suggestion that Petitioner was required to address the
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`unit dose and maximum daily total dose limitations entirely separate from one
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`another is wrong, and appears to have caused the Board to overlook or
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`misapprehend Petitioner’s argument regarding the maximum daily dose limitation.
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`Petitioner does not dispute that the unit dose range and the 20 mg maximum daily
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`dosage are separate limitations in the ‘166 Patent claims. However, as discussed
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`above, because the SNDA taught “single doses” per day, Petition at 41, the unit
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`dosage and the maximum daily total were one and the same in the SNDA. Thus,
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`the Petitioner pointed to the size of the “single” dose in the SNDA to account for
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`both the unit dose and the maximum total dose per day. Petition at 41 (claim
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`chart); supra Section II.A.1.
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`Petitioner’s Ground 2 claim chart confirms exactly that, Petition at 41, and
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`the Patent Owner’s argument that Petitioner ignored the maximum daily total
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`limitation has no merit. Petitioner’s treatment of this claim limitation jointly with
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`10
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`
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`the unit dose limitation was both sufficient and persuasive, because Petitioner’s
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`analysis was predicated on the commonsense notion that maximum daily total for a
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`single 10 mg dose per day of sildenafil is necessarily 10 mg, which is less than the
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`20 mg per day maximum claimed in the ‘166 Patent. That was the precise reason
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`why Petitioner placed particular the emphasis on the “single” and “10” mg in the
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`Ground 2 claim chart, Petition at 41, and it the precise reason why every other
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`evidentiary citation in Ground 2 necessarily referred to a single daily dose.
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`Petitioner therefore adequately accounted for the maximum per day dose limitation
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`in Claim 1 of the ‘166 Patent.
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`4.
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`Identifying the maximum dose of a drug for therapeutic efficacy
`was well known in the art before April 30, 1999.
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`A person of ordinary skill in the art would have readily understood the
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`concept of a drug’s “therapeutic index”, the margin between the doses of a drug
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`required to produce a therapeutic effect versus doses that cause toxicity. Such an
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`artisan would have known that increasing the dose of a drug beyond the peak of
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`therapeutic efficacy ceases to provide therapeutic benefit and, instead, produces
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`undue toxicity. As set forth in the Petition (pp. 12-14) and Hellstrom Declaration
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`(Exh. 1005, paras. 54-62), it was routine practice in the art to utilize dose-response
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`curves to generate the therapeutic index which increases with dosage until reaching
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`a peak, or maximum, therapeutic efficacy. A person of ordinary skill would have
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`11
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`identified the top of the therapeutic dose-response curve (i.e., the maximum dose)
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`and would have understood that additional increases in the dose result in little to no
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`benefit when the top of the curve is reached.
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`III. CONCLUSION
`It appears the Board understood that the Petitioner argued that the known
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`higher potency of tadalafil would suggest using a lower dose than taught in the
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`SNDA, but did not appreciate that (a) the Petitioner relied on the SNDA to teach a
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`“single dose” per day of sildenafil that is both the unit dose and the maximum
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`daily total near or under 20 mg, and (b) as such, a person of ordinary skill in the
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`art would have been motivated to reduce the size of a single daily dose of more
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`potent tadalafil to an amount lower than the 20 mg maximum daily claimed by the
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`Patent Owner. Petitioner submits that the Board overlooked or misapprehended
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`the points noted above. Thus, Petitioner respectfully submits that rehearing is
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`warranted and should be granted to institute the requested inter partes review
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`against claims 1-12 of the ‘166 Patent.
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`12
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`
`
`Respectfully submitted,
`/Bryan P. Collins/
`Bryan P. Collins, Reg. No. 43,560
`Pillsbury Winthrop Shaw Pittman LLP
`1650 Tysons Blvd, Suite 1400
`McLean, VA 22102
`Tel. No. 703.770.7538
`Fax No. 703.770.7901
`
`
`
`Date: October 3, 2016
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`13
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`
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`CERTIFICATE OF SERVICE
`I hereby certify that a true copy of the REQUEST FOR REHEARING
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`UNDER 37 C.F.R. §42.71 was served in its entirety by email this 3rd day of
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`October 2016 on the attorney of record of ICOS Corp., owner of the subject patent,
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`as indicated below:
`
`Mark J. Feldstein
`Joshua Goldberg
`Yieyie Yang
`Finnegan, Henderson, Farabow, Garrett & Dunner, LLP
`901 New York Avenue, NW
`Washington, DC 20001-4413
`ICOS-IPRs@finnegan.com
`
`
`
`Mark J. Stewart
`Dan L. Wood
`Eli Lilly and Company
`Lilly Corporate Center
`Indianapolis, IN 46285
`ICOS-IPRs@finnegan.com
`
`
`
`/Bryan P. Collins/
`Bryan P. Collins, Reg. No. 43,560
`Pillsbury Winthrop Shaw Pittman LLP
`1650 Tysons Blvd, Suite 1400
`McLean, VA 22102
`Tel. No. 703.770.7538
`Fax No. 703.770.7901
`
`
`
`14
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