UNITED STA IBS p A IBNT AND TRADEMARK OFFICE
`
`UNITED STA TES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`Address: COMMISSIONER FOR PATENTS
`P.O. Box 1450
`Alexandria., Virginia 22313-1450
`www.uspto.gov
`
`APPLICATION NO.
`
`FILING DATE
`
`FIRST NAMED INVENTOR
`
`ATTORNEY DOCKET NO.
`
`CONFIRMATION NO.
`
`13/768,906
`
`02/15/2013
`
`MeharManku
`
`88896-8004.USl0
`
`4793
`
`05/24/2013
`7590
`113568
`Perkins Coie LLP - Amarin Corporation PLC
`1201 Third Avenue
`Suite 4900
`Seattle, WA 98101
`
`EXAMINER
`
`SASAN, ARADHANA
`
`ART UNIT
`
`PAPER NUMBER
`
`1615
`
`NOTIFICATION DATE
`
`DELIVERY MODE
`
`05/24/2013
`
`ELECTRONIC
`
`Please find below and/or attached an Office communication concerning this application or proceeding.
`
`The time period for reply, if any, is set in the attached communication.
`
`Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
`following e-mail address(es):
`patentprocurement@perkinscoie.com
`
`PTOL-90A (Rev. 04/07)
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1038, p. 1 of 22
`
`

`

`Office Action Summary
`
`AIA (First Inventor to File)
`Status
`No
`-- The MAILING DA TE of this communication appears on the cover sheet with the correspondence address -(cid:173)
`Period for Reply
`
`Examiner
`ARADHANA SASAN
`
`Art Unit
`1615
`
`Application No.
`13/768,906
`
`Applicant(s)
`MANKU ET AL.
`
`A SHORTENED STATUTORY PERIOD FOR REPLY IS SET TO EXPIRE ;J. MONTH(S) OR THIRTY (30) DAYS,
`WHICHEVER IS LONGER, FROM THE MAILING DATE OF THIS COMMUNICATION.
`Extensions of time may be available under the provisions of 37 CFR 1.136(a). In no event, however, may a reply be timely filed
`after SIX (6) MONTHS from the mailing date of this communication.
`If NO period for reply is specified above, the maximum statutory period will apply and will expire SIX (6) MONTHS from the mailing date of this communication.
`Failure to reply within the set or extended period for reply will, by statute, cause the application to become ABANDONED (35 U.S.C. § 133).
`Any reply received by the Office later than three months after the mailing date of this communication, even if timely filed, may reduce any
`earned patent term adjustment. See 37 CFR 1.704(b).
`
`Status
`1 )~ Responsive to communication(s) filed on 15 February 2013.
`0 A declaration(s)/affidavit(s) under 37 CFR 1.130(b) was/were filed on __ .
`2a)0 This action is FINAL.
`2b)~ This action is non-final.
`3)0 An election was made by the applicant in response to a restriction requirement set forth during the interview on
`__ ; the restriction requirement and election have been incorporated into this action.
`4)0 Since this application is in condition for allowance except for formal matters, prosecution as to the merits is
`closed in accordance with the practice under Ex parte Quayle, 1935 C.D. 11, 453 O.G. 213.
`
`Disposition of Claims
`5)~ Claim(s) 1-19 is/are pending in the application.
`5a) Of the above claim(s) __ is/are withdrawn from consideration.
`6)0 Claim(s) __ is/are allowed.
`7)~ Claim(s) 1-19 is/are rejected.
`8)0 Claim(s) __ is/are objected to.
`9)0 Claim(s) __ are subject to restriction and/or election requirement.
`* If any claims have been determined allowable, you may be eligible to benefit from the Patent Prosecution Highway program at a
`participating intellectual property office for the corresponding application. For more information, please see
`http:ilwww.usoto.gov/patents/init events/pph/index.isp or send an inquiry to PPHfeedback(wuspto.aov.
`
`Application Papers
`10)0 The specification is objected to by the Examiner.
`11 )~ The drawing(s) filed on 15 Februarv2013 is/are: a)~ accepted or b)O objected to by the Examiner.
`Applicant may not request that any objection to the drawing(s) be held in abeyance. See 37 CFR 1.85(a).
`Replacement drawing sheet(s) including the correction is required if the drawing(s) is objected to. See 37 CFR 1.121 (d).
`
`Priority under 35 U.S.C. § 119
`12)0 Acknowledgment is made of a claim for foreign priority under 35 U.S.C. § 119(a)-(d) or (f).
`Certified copies:
`a)O All b)O Some* c)O None of the:
`Certified copies of the priority documents have been received.
`1.0
`Certified copies of the priority documents have been received in Application No. __ .
`2.0
`Copies of the certified copies of the priority documents have been received in this National Stage
`3.0
`application from the International Bureau (PCT Rule 17.2(a)).
`* See the attached detailed Office action for a list of the certified copies not received.
`Interim copies:
`a)O All b)O Some c)O None of the:
`
`Interim copies of the priority documents have been received.
`
`Attachment{s)
`1) ~ Notice of References Cited (PTO-892)
`
`2) ~ Information Disclosure Statement(s) (PTO/SB/08)
`Paper No(s)/Mail Date 03/07/13.
`
`U.S. Patent and Trademark Office
`PTOL-326 (Rev. 03-13)
`
`3) 0 Interview Summary (PTO-413)
`Paper No(s)/Mail Date. __ .
`4) 0 Other: __ .
`
`Office Action Summary
`
`Part of Paper No./Mail Date 20130518
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1038, p. 2 of 22
`
`

`

`Application/Control Number: 13/768,906
`Art Unit: 1615
`
`Page 2
`
`DETAILED ACTION
`
`Status of Application
`
`1.
`
`Claims 1-19 are included in the prosecution.
`
`Information Disclosure Statement
`
`2.
`
`The information disclosure statement (IDS) filed on 03/07/2013 is acknowledged.
`
`The submission is in compliance with the provisions of 37 CFR 1.97 and 1.98.
`
`Accordingly, the examiner is considering the information disclosure statement.
`
`See attached copy of PTO-1449.
`
`Claim Rejections - 35 USC § 103
`
`3.
`
`The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all
`
`obviousness rejections set forth in this Office action:
`
`(a) A patent may not be obtained though the invention is not identically disclosed or described as set
`forth in section 102 of this title, if the differences between the subject matter sought to be patented and
`the prior art are such that the subject matter as a whole would have been obvious at the time the
`invention was made to a person having ordinary skill in the art to which said subject matter pertains.
`Patentability shall not be negatived by the manner in which the invention was made.
`The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148
`
`USPQ 459 (1966), that are applied for establishing a background for determining
`
`obviousness under 35 U.S.C. 103(a) are summarized as follows:
`
`1.
`
`2.
`
`3.
`
`4.
`
`Determining the scope and contents of the prior art.
`
`Ascertaining the differences between the prior art and the claims at issue.
`
`Resolving the level of ordinary skill in the pertinent art.
`
`Considering objective evidence present in the application indicating
`
`obviousness or nonobviousness.
`
`4.
`
`Claims 1-12 and 14-19 are rejected under 35 U.S.C. 103(a) as being
`
`unpatentable over Katayama et al. (Prag. Med. 2001; 21: 457-467 - English
`
`Translation) in view of Davidson et al. (Clinical Therapeutics Vol. 29, Number 7, 2007,
`
`pp. 1354-1367) and Saito et al. (Atherosclerosis 200 (2008) 135-140).
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1038, p. 3 of 22
`
`

`

`Application/Control Number: 13/768,906
`Art Unit: 1615
`
`Page 3
`
`The claimed invention is a method of treating mixed dyslipidemia in a subject on
`
`statin therapy comprising, administering to the subject a pharmaceutical composition
`
`comprising about 2500 mg to 5000 mg per day of ethyl eicosapentaenoate and not
`
`more than about 5% docosahexaenoic acid or its esters, by weight of all fatty acids, to
`
`effect a reduction in fasting triglycerides of at least 10% and a reduction in LDL-C
`
`compared to placebo control.
`
`Katayama et al. teach a method of lowering triglycerides in a subject comprising
`
`administering three capsules containing 300 mg each of ethyl eicosapentaenoate
`
`(EPADEL®). The administration is 3 times a day for a daily dose of 2700 mg. The
`
`subjects have a baseline triglyceride level of at least 150 mg/di (Page 3, section
`
`"Method", Page 8, last paragraph - "Triglyceride", Figure 3 "Transition in serum
`
`triglyceride"). The treatment period is 3 months (or 12 weeks), after which the subjects
`
`show 25.1 ± 3.0% reduction in triglyceride level (Figure 3). The baseline HDL-C level is
`
`49.1 ± 1.2 mg/dl before treatment (Page 9, "HDL-Cholesterol and Figure 4).
`
`Katayama et al. do not expressly teach that the subject is on statin therapy.
`
`Davidson et al. teach that adding prescription omega-3-acid ethyl esters (P-OM3
`
`- at 4g/d; Lovaza™, formerly Omacor®) to stable statin therapy in patients with
`
`persistent hypertriglyceridemia was associated with significant reductions in triglyceride
`
`(TG) levels (29.5% vs 6.3%) and very-low-density lipoprotein cholesterol (VLDL-C)
`
`(27.5% vs 7.2%), and a significant reduction in the total cholesterol:HDL-C ratio (9.6%
`
`vs 0.7%) (all, P < 0.001 vs placebo) (Page 1354). Davidson et al. teach that under
`
`hypertriglyceridemic conditions, VLDL-C becomes an important component of non-HDL(cid:173)
`
`C, and that statin treatment alone may be insufficient to achieve non-HDL-C targets
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1038, p. 4 of 22
`
`

`

`Application/Control Number: 13/768,906
`Art Unit: 1615
`
`Page 4
`
`(Page 1355). Each 1-g capsule of P-OM3 contains highly concentrated ethyl esters of
`
`omega-3 fatty acids, primarily eicosapentaenoic acid (EPA) 465 mg and
`
`docosahexaenoic acid (DHA) 375 mg (Page 1355). Table II (Page 1360) shows the lipid
`
`and lipoprotein results wherein TG reduction was 29.5% for patients receiving the
`
`combination vs. 6.35 reduction for patients on statin only, non-HDL-C reduction was
`
`9.0% vs. 2.2%, VLDL-C reduction was 27.5% vs. 7.2% respectively, total cholesterol
`
`(TC) reduction was 4.8% vs. 1.7%), the TC/HDL-C ratio reduction was 9.6% vs. 0.7%,
`
`and reduction in Apolipprotein B (Apo-B) was 4.2% and 1.9% respectively.
`
`Davidson et al. do not expressly teach a reduction in LDL-C compared to placebo
`
`control.
`
`Saito et al. teach that administration of 1800 mg per day of EPA ethylester in
`
`combination with a statin (Page 136, Section 2.2 "Procedures") in patients with high TG
`
`and high TC led to a significant reduction in TG (23%) which was even significant when
`
`compared to individuals on statin alone (18% decrease), and a significant decrease in
`
`LDL-C (20%) (Table 2, Page 138).
`
`It would have been obvious to one of ordinary skill in the art at the time the
`
`invention was made to use the method of lowering triglycerides in a subject having a
`
`baseline triglyceride level of at least 150 mg/di comprising administering capsules
`
`containing 300 mg each of ethyl eicosapentaenoate for a 25.1 + 3.0% reduction in
`
`triglyceride level, as taught by Katayama et al., in view of the method of adding
`
`prescription omega-3-acid ethyl esters at 4g/d to stable statin therapy in patients with
`
`persistent hypertriglyceridemia in order to achieve significant reductions in TG levels
`
`(29.5% vs 6.3%), VLDL-C levels (27.5% vs 7.2%), and in the total cholesterol:HDL-C
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1038, p. 5 of 22
`
`

`

`Application/Control Number: 13/768,906
`Art Unit: 1615
`
`Page 5
`
`ratio (9.6% vs 0.7%) (all, P < 0.001 vs placebo), as taught by Davidson et al., in view of
`
`the administration of 1800 mg per day of EPA ethylester in combination with a statin in
`
`patients with high TG and high TC in order to achieve significant reduction in TG (23%)
`
`and in LDL-C (20%), as taught by Saito et al., and produce the instant invention.
`
`One of ordinary skill in the art would have been motivated to do this because all
`
`the references are drawn to methods of treating patients having high TG levels. Both
`
`Davidson et al. and Saito et al. are drawn to methods of treating patients having high
`
`TG and TC levels, as well as the co-administration of statins and ethyl EPA. The result
`
`of achieving a reduction in LDL-C compared to control subjects would have been
`
`expected based on the teaching by Saito et al. unless there is evidence of criticality or
`
`unexpected results.
`
`From the teachings of the references, it is apparent that one of ordinary skill in
`
`the art would have had a reasonable expectation of success in producing the claimed
`
`invention. Therefore, the invention as a whole would have been prima facie obvious to
`
`one of ordinary skill in the art at the time the invention was made, as evidenced by the
`
`references, especially in the absence of evidence to the contrary.
`
`Regarding instant claims 1-7, 9-12 and 14-19, the limitations of the method would
`
`have been obvious over the method of treatment taught by Katayama et al. (Page 3,
`
`section "Method", Page 8, last paragraph - "Triglyceride", Figure 3 "Transition in serum
`
`triglyceride," Page 9, "HDL-Cholesterol and Figure 4); Davidson et al. (Page 1354, Page
`
`1355, Table 11 -Page 1360); and Saito et al. (Page 136, Section 2.2 "Procedures" and
`
`Table 2, Page 138).
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1038, p. 6 of 22
`
`

`

`Application/Control Number: 13/768,906
`Art Unit: 1615
`
`Page 6
`
`Regarding instant claim 8, the limitation of reduction in hs-CRP would have been
`
`obvious over the decrease in levels of plasma C-reactive protein (CRP) known in the
`
`prior art (by Satoh et al.) as disclosed by Saito et al. (Page 139, right hand column).
`
`Although the patient population treated in the prior art discussed by Saito et al. is
`
`different, one of ordinary skill in the art would expect a reduction in plasma CRP and hs(cid:173)
`
`CRP when co-administering statins and ethyl EPA since the prior art teaches a
`
`reduction in this marker of inflammation which is a risk factor for cardiovascular events
`
`(Saito et al. - Page 139, right hand column).
`
`5.
`
`Claim 13 is rejected under 35 U.S.C. 103(a) as being unpatentable over
`
`Katayama et al. (Prag. Med. 2001; 21: 457-467 - English Translation) in view of
`
`Davidson et al. (Clinical Therapeutics Vol. 29, Number 7, 2007, pp. 1354-1367) Saito
`
`et al. (Atherosclerosis 200 (2008) 135-140) and Anderson (The American Journal of
`
`Cardiology, 2008;101 :23F-33F).
`
`Katayama et al., Davidson et al. and Saito et al. are discussed above.
`
`These references do not expressly teach a reduction in lipoprotein associated
`
`phospholipase A2 (Lp-PLA2) compared to placebo control.
`
`Anderson teaches that Lp-PLA2 is an independent predictor of coronary artery
`
`disease and is especially appealing because of its vascular specificity, which directly
`
`derives from its role in plaque pathophysiology (Abstract). Anderson discloses that: "An
`
`increasingly prevalent group at intermediate risk shown to benefit from Lp-PLA2 risk
`
`modification is the population with the cardiovascular metabolic syndrome, clinically
`
`identified as overweight patients with features of mixed dyslipidemia, dysglycemia, and
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1038, p. 7 of 22
`
`

`

`Application/Control Number: 13/768,906
`Art Unit: 1615
`
`Page 7
`
`hypertension. An additional application supported by these studies is further risk
`
`stratification of high- (often secondary-) risk patients into a group at very high risk, for
`
`whom a more aggressive target for low-density lipoprotein of <70 mg/dl (1 mg/dl
`
`0.02586 mmol/L) is now recommended as a reasonable therapeutic goal" (Abstract).
`
`It would have been obvious to one of ordinary skill in the art at the time the
`
`invention was made to use the method of lowering triglycerides in a subject having a
`
`baseline triglyceride level of at least 150 mg/di comprising administering capsules
`
`containing 300 mg each of ethyl eicosapentaenoate for a 25.1 + 3.0% reduction in
`
`triglyceride level, as taught by Katayama et al., in view of the method of adding
`
`prescription omega-3-acid ethyl esters at 4g/d to stable statin therapy in patients with
`
`persistent hypertriglyceridemia in order to achieve significant reductions in TG levels
`
`(29.5% vs 6.3%), VLDL-C levels (27.5% vs 7.2%), and in the total cholesterol:HDL-C
`
`ratio (9.6% vs 0.7%) (all, P < 0.001 vs placebo), as taught by Davidson et al., in view of
`
`the administration of 1800 mg per day of EPA ethylester in combination with a statin in
`
`patients with high TG and high TC in order to achieve significant reduction in TG (23%)
`
`and in LDL-C (20%), as taught by Saito et al., and further in view of the teaching that
`
`Lp-PLA2 is an independent predictor of coronary artery disease, as taught by Anderson,
`
`and produce the instant invention.
`
`One of ordinary skill in the art would have found it obvious to look to the teaching
`
`of Lp-PLA2 as a predictor of coronary artery disease by Anderson because the patient
`
`population is the same as addressed by both Davidson et al. and Saito et al. The result
`
`of achieving a reduction in Lp-PLA2 compared to placebo control would have been
`
`expected unless there is evidence of criticality or unexpected results.
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1038, p. 8 of 22
`
`

`

`Application/Control Number: 13/768,906
`Art Unit: 1615
`
`Page 8
`
`Regarding instant claim 13, the limitation of a reduction in Lp-PLA2 compared to
`
`placebo control would have been obvious over the methods of treatment taught by
`
`Davidson et al. (Page 1354, Page 1355, Table II -Page 1360); Saito et al. (Page 136,
`
`Section 2.2 "Procedures" and Table 2, Page 138); and the teaching that Lp-PLA2 is an
`
`independent predictor of coronary artery disease and a more specific vascular predictor
`
`than CRP, as taught by Anderson (Abstract).
`
`4.
`
`Claims 1-12 and 14-19 are rejected under 35 U.S.C. 103(a) as being
`
`unpatentable over Rongen et al. (US 2007/0191467 A 1) in view of Saito et al.
`
`(Atherosclerosis 200 (2008) 135-140).
`
`Rongen et al. teach a method of lipid therapy, including treating mixed
`
`dyslipidemia, comprising providing a subject group having a baseline triglyceride level of
`
`200 to 499 mg/di, and reducing the triglyceride level and the non-high-density
`
`lipoprotein cholesterol (non-HDL-C) level of the subject group as compared to treatment
`
`with a 3-hydroxy-3-methyl glutaryl coenzyme A (HMG CoA) inhibitor alone, by
`
`administering to the subject group an effective amount of an HMG CoA inhibitor and a
`
`composition comprising omega-3 fatty acids (Abstract, Page 2, [0014], Page 4, [0038] to
`
`Page 5, [0043] and claims 1-20). Ethyl esters of omega-3 fatty acids, including EPA or
`
`DHA are disclosed (Page 6, [0067] to Page 7, [0072]). The ratio of EPA:DHA may be
`
`from 99:1 to 1 :99 (Page 6, [0070]). The omega-3 fatty acids can be administered in a
`
`daily amount of from about 0.1 g to about 10 g, and in one embodiment, the omega-3
`
`fatty acids are administered in an amount up to 4 g/day (Page 7, [0076]). Statins are
`
`disclosed (Page 7, [0077] - [0086]). The examples show a clinical study where a
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1038, p. 9 of 22
`
`

`

`Application/Control Number: 13/768,906
`Art Unit: 1615
`
`Page 9
`
`randomized, double-blind, placebo-controlled study was used to assess the efficacy and
`
`safety of combined OMACOR® and simvastatin therapy in hypertriglyceridemic subjects
`
`(Page 8, [0089] - [0093] and Table 1 ).
`
`Rongen et al. do not expressly teach a reduction in LDL-C compared to placebo
`
`control.
`
`Saito et al. teach that administration of 1800 mg per day of EPA ethylester in
`
`combination with a statin (Page 136, Section 2.2 "Procedures") in patients with high TG
`
`and high TC led to a significant reduction in TG (23%) which was even significant when
`
`compared to individuals on statin alone (18% decrease), and a significant decrease in
`
`LDL-C (20%) (Table 2, Page 138).
`
`It would have been obvious to one of ordinary skill in the art at the time the
`
`invention was made to use the method of treating mixed dyslipidemia, comprising
`
`providing a subject group having a baseline triglyceride level of 200 to 499 mg/di, and
`
`reducing the triglyceride level and the non-high-density lipoprotein cholesterol (non(cid:173)
`
`HDL-C) level of the subject group as compared to treatment with a statin alone, by
`
`administering to the subject group an effective amount of a statin and a composition
`
`comprising omega-3 fatty acids in order to reduce the triglyceride level, as taught by
`
`Rongen et al., in view of the administration of 1800 mg per day of EPA ethylester in
`
`combination with a statin in patients with high TG and high TC in order to achieve
`
`significant reduction in TG (23%) and in LDL-C (20%), as taught by Saito et al., and
`
`produce the instant invention.
`
`One of ordinary skill in the art would have been motivated to do this because
`
`both the references are drawn to methods of treating patients having high TG levels.
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1038, p. 10 of 22
`
`

`

`Application/Control Number: 13/768,906
`Art Unit: 1615
`
`Page 1 0
`
`Both Rongen et al. and Saito et al. are drawn to methods of treating patients having
`
`high TG and TC levels, as well as the co-administration of statins and ethyl EPA. The
`
`result of achieving a reduction in LDL-C compared to control subjects would have been
`
`expected based on the teaching by Saito et al. unless there is evidence of criticality or
`
`unexpected results.
`
`From the teachings of the references, it is apparent that one of ordinary skill in
`
`the art would have had a reasonable expectation of success in producing the claimed
`
`invention. Therefore, the invention as a whole would have been prima facie obvious to
`
`one of ordinary skill in the art at the time the invention was made, as evidenced by the
`
`references, especially in the absence of evidence to the contrary.
`
`Regarding instant claims 1-7, 9-12 and 14-19, the limitations of the method would
`
`have been obvious over the method of treatment taught by Rongen et al. (Abstract,
`
`Page 2, [0014], Page 4, [0038] to Page 5, [0043], claims 1-20, Page 6, [0067] to Page
`
`7, [0072], [0076] - [0086], Page 8, [0089] - [0093] and Table 1 ); and Saito et al. (Page
`
`136, Section 2.2 "Procedures" and Table 2, Page 138).
`
`Regarding instant claim 8, the limitation of reduction in hs-CRP would have been
`
`obvious over the decrease in levels of plasma C-reactive protein (CRP) known in the
`
`prior art (by Satoh et al.) as disclosed by Saito et al. (Page 139, right hand column).
`
`Although the patient population treated in the prior art discussed by Saito et al. is
`
`different, one of ordinary skill in the art would expect a reduction in plasma CRP and hs(cid:173)
`
`CRP when co-administering statins and ethyl EPA since the prior art teaches a
`
`reduction in this marker of inflammation which is a risk factor for cardiovascular events
`
`(Saito et al. - Page 139, right hand column).
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1038, p. 11 of 22
`
`

`

`Application/Control Number: 13/768,906
`Art Unit: 1615
`
`Page 11
`
`5.
`
`Claim 13 is rejected under 35 U.S.C. 103(a) as being unpatentable over Rongen
`
`et al. (US 2007/0191467 A 1) in view of Saito et al. (Atherosclerosis 200 (2008) 135-
`
`140) and Anderson (The American Journal of Cardiology, 2008;101 :23F-33F).
`
`Rongen et al. and Saito et al. are discussed above.
`
`These references do not expressly teach a reduction in lipoprotein associated
`
`phospholipase A2 (Lp-PLA2) compared to placebo control.
`
`Anderson teaches that Lp-PLA2 is an independent predictor of coronary artery
`
`disease and is especially appealing because of its vascular specificity, which directly
`
`derives from its role in plaque pathophysiology (Abstract). Anderson discloses that: "An
`
`increasingly prevalent group at intermediate risk shown to benefit from Lp-PLA2 risk
`
`modification is the population with the cardiovascular metabolic syndrome, clinically
`
`identified as overweight patients with features of mixed dyslipidemia, dysglycemia, and
`
`hypertension. An additional application supported by these studies is further risk
`
`stratification of high- (often secondary-) risk patients into a group at very high risk, for
`
`whom a more aggressive target for low-density lipoprotein of <70 mg/dl (1 mg/dl
`
`0.02586 mmol/L) is now recommended as a reasonable therapeutic goal" (Abstract).
`
`It would have been obvious to one of ordinary skill in the art at the time the
`
`invention was made to use the method of treating mixed dyslipidemia, comprising
`
`providing a subject group having a baseline triglyceride level of 200 to 499 mg/di, and
`
`reducing the triglyceride level and the non-high-density lipoprotein cholesterol (non(cid:173)
`
`HDL-C) level of the subject group as compared to treatment with a statin alone, by
`
`administering to the subject group an effective amount of a statin and a composition
`
`comprising omega-3 fatty acids in order to reduce the triglyceride level, as taught by
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1038, p. 12 of 22
`
`

`

`Application/Control Number: 13/768,906
`Art Unit: 1615
`
`Page 12
`
`Rongen et al., in view of the administration of 1800 mg per day of EPA ethylester in
`
`combination with a statin in patients with high TG and high TC in order to achieve
`
`significant reduction in TG (23%) and in LDL-C (20%), as taught by Saito et al., and
`
`further in view of the teaching that Lp-PLA2 is an independent predictor of coronary
`
`artery disease, as taught by Anderson, and produce the instant invention.
`
`One of ordinary skill in the art would have found it obvious to look to the teaching
`
`of Lp-PLA2 as a predictor of coronary artery disease by Anderson because the patient
`
`population is the same as addressed by both Davidson et al. and Saito et al. The result
`
`of achieving a reduction in Lp-PLA2 compared to placebo control would have been
`
`expected unless there is evidence of criticality or unexpected results.
`
`Regarding instant claim 13, the limitation of a reduction in Lp-PLA2 compared to
`
`placebo control would have been obvious over the methods of treatment taught by
`
`Rongen et al. (Abstract, Page 2, [0014], Page 4, [0038] to Page 5, [0043], claims 1-20,
`
`Page 6, [0067] to Page 7, [0072], [0076] - [0086], Page 8, [0089] - [0093] and Table 1 );
`
`Saito et al. (Page 136, Section 2.2 "Procedures" and Table 2, Page 138); and the
`
`teaching that Lp-PLA2 is an independent predictor of coronary artery disease and a
`
`more specific vascular predictor than CRP, as taught by Anderson (Abstract).
`
`Double Patenting
`
`The nonstatutory double patenting rejection is based on a judicially created
`6.
`doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the
`unjustified or improper timewise extension of the "right to exclude" granted by a patent
`and to prevent possible harassment by multiple assignees. A nonstatutory
`obviousness-type double patenting rejection is appropriate where the conflicting claims
`are not identical, but at least one examined application claim is not patentably distinct
`from the reference claim(s) because the examined application claim is either anticipated
`by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140
`F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1038, p. 13 of 22
`
`

`

`Application/Control Number: 13/768,906
`Art Unit: 1615
`
`Page 13
`
`USPQ2d 2010 (Fed. Cir. 1993); In re Langi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir.
`1985); In re Van Ornum, 686 F.2d 937,214 USPQ 761 (CCPA 1982); In re Vogel, 422
`F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ
`644 (CCPA 1969).
`A timely filed terminal disclaimer in compliance with 37 CFR 1.321 (c) or 1.321 (d)
`may be used to overcome an actual or provisional rejection based on a nonstatutory
`double patenting ground provided the conflicting application or patent either is shown to
`be commonly owned with this application, or claims an invention made as a result of
`activities undertaken within the scope of a joint research agreement.
`Effective January 1, 1994, a registered attorney or agent of record may sign a
`terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with
`37 CFR 3.73(b).
`
`7.
`
`Claims 1-19 are provisionally rejected on the ground of nonstatutory
`
`obviousness-type double patenting as being unpatentable over claims 1-10, 12-15, 20-
`
`22 and 24-25 of copending Application No. 12/815,569 (the '569 Application).
`
`Although the conflicting claims are not identical, they are not patentably distinct
`
`from each other because they are drawn to a method of lowering TG in a patient
`
`population on statin therapy the method comprising administering ethyl EPA.
`
`The difference is that instant claims recite treating "mixed dyslipidemia" whereas
`
`claims of the '569 Application recite the subject having baseline fasting triglycerides of
`
`about 200 mg/di to about 500 mg/di. However, one of ordinary skill in the art would
`
`know that a patient on statin therapy requires TG lowering and would therefore find it
`
`obvious to combine the treatment method of statin therapy with ethyl EPA therapy.
`
`Please note that the projected issue date for this application is 06/04/2013.
`
`However, since the patent (US 8,455,472) has not issued yet, a provisional
`
`obviousness-type double patenting rejection is made at this time
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1038, p. 14 of 22
`
`

`

`Application/Control Number: 13/768,906
`Art Unit: 1615
`
`Page 14
`
`8.
`
`Claims 1-19 are provisionally rejected on the ground of nonstatutory
`
`obviousness-type double patenting as being unpatentable over claims 19-33 of
`
`copending Application No. 13/124,628 (the '628 Application).
`
`Although the conflicting claims are not identical, they are not patentably distinct
`
`from each other because they are drawn to a method of lowering TG in a patient
`
`population on statin therapy the method comprising administering ethyl EPA.
`
`The difference is that instant claims recite treating "mixed dyslipidemia" whereas
`
`claims of the '628 Application recite the subject having baseline fasting triglycerides of
`
`about 200 mg/di to about 500 mg/di and recite a specific statin (rosuvastatin). However,
`
`one of ordinary skill in the art would know that a patient on statin therapy requires TG
`
`lowering and would therefore find it obvious to combine the treatment method of statin
`
`therapy with ethyl EPA therapy. The limitation of a specific statin in the '628 Application
`
`renders obvious the limitation of "statin" in the instant claims.
`
`This is a provisional obviousness-type double patenting rejection because the
`
`conflicting claims have not in fact been patented.
`
`9.
`
`Claims 1-19 are provisionally rejected on the ground of nonstatutory
`
`obviousness-type double patenting as being unpatentable over claims 21-27 of
`
`copending Application No. 13/266,085 (the '085 Application).
`
`Although the conflicting claims are not identical, they are not patentably distinct
`
`from each other because they are drawn to a method of lowering TG in a patient
`
`population on statin therapy the method comprising administering EPA.
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1038, p. 15 of 22
`
`

`

`Application/Control Number: 13/768,906
`Art Unit: 1615
`
`Page 15
`
`The difference is that instant claims recite ethyl EPA whereas claims of the '085
`
`Application recite the generic "EPA". However, one of ordinary skill in the art would
`
`know that the ethyl EPA of instant claims renders obvious the EPA limitation in claims of
`
`the '085 Application. The limitation of specific statins in the '085 Application renders
`
`obvious the limitation of "statin" in the instant claims.
`
`This is a provisional obviousness-type double patenting rejection because the
`
`conflicting claims have not in fact been patented.
`
`10.
`
`Claims 1-19 are provisionally rejected on the ground of nonstatutory
`
`obviousness-type double patenting as being unpatentable over claims 1-17 of
`
`copending Application No. 13/359, 114 (the '114 Application).
`
`Although the conflicting claims are not identical, they are not patentably distinct
`
`from each other because they are drawn to a method of lowering TG in a patient
`
`population on statin therapy the method comprising administering ethyl EPA.
`
`The difference is that instant claims recite treating "mixed dyslipidemia" whereas
`
`claims of the '114 Application recite the subject having baseline fasting triglycerides of
`
`about 200 mg/di to less than 500 mg/di. However, one of ordinary skill in the art would
`
`know that a patient on statin therapy requires TG lowering and would therefore find it
`
`obvious to combine the treatment method of statin therapy with ethyl EPA therapy.
`
`This is a provisional obviousness-type double patenting rejection be