DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/11/24 has been entered.
Election/Restrictions – Retained for the Record
Applicant’s election without traverse of SEQ ID NO:13 as the species of inhibitor of NTCP, and pegylated interferon as the further active ingredient, in the reply filed on 11/20/23 is acknowledged.
To clarify the election of species of inhibitor of NTCP, the examiner telephoned applicant’s attorney on 12/11/23 and was told that the elected species of inhibitor of NTCP was the peptide of SEQ ID NO:13 with a myristoyl attached at the N-terminus of this peptide. A telephone interview summary was previously attached.
Claims 11-14 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/20/23.
Claim 17, which includes the elected pegylated interferon as a further active ingredient but also includes in various alternatives non-elected further active ingredients, had previously been examined only as to the combination that includes the elected SEQ ID NO:13 and pegylated interferon.
Claim Status
Claims 1, 6, 7, 9, 18-20, 26-27 are pending.
Claims 2-5, 8, 10-17, 21-25, 28-29 are cancelled.
Claims 11-14 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species, there being no allowable generic or linking claim.
Claims 1, 6, 7, 9, 18-20, 26-27 have been examined.
Claims 1, 6, 7, 9, 18-20, 26-27 are rejected.
Priority
The instant application, filed 03/23/2021 and having 1 RCE-type filing therein is a Divisional of 15514878 , filed 03/28/2017, now abandoned
15514878 is a National Stage entry of PCT/EP2015/073173 , International Filing Date: 10/07/2015
claims foreign priority to 14187865.2, filed 10/07/2014.
Information Disclosure Statement
The Examiner has considered the references provided in the 11/20/25 Information Disclosure Statement, and provides a signed and dated copy of such herewith.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated 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 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 6, 7, 9, 18-20, 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Publication No. 20110020397, Mier and Urban, published 1/27/2011 (MU), previously applied, in view of Cooksley et al., “Peginterferon α-2a (40 kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B”, Jl. Viral Hepatitis, 2003, 10, 298-305 (Cooksley), previously provided, Excerpt from page 2034, Part 88, of Remington, The Science and Practice of Pharmacy, David B. Troy, Ed., 21st Edition, 2006, Lippincott Williams and Wilkins, Baltimore MD (RemE), as evidenced by Kuk et al., Am J Epidemiol 2009;170:456–463 (Kuk) and Treating Hepatitis With Interferon, 2010, 7 pages, downloaded from www.everydayhealth.com (Everydayhealth), previously provided.
Claim 1 is directed to a method of treating an HBV or HDV infection, hepatitis B, chronic hepatitis B, hepatitis D, or chronic hepatitis D in a subject in need thereof comprising administering to the subject a composition or combination comprising an inhibitor having an amino acid sequence as set forth in SEQ ID NO:13 and a pegylated interferon alpha, wherein the inhibitor is administered at a unit dose of 10 mg per day, and the pegylated interferon alpha is administered at a unit dose of 180 ug per week (11/20/25 claim amendment removing inhibitor unit doses of “2 mg, 5 mg,”).
This rejection is directed to the elected species of SEQ ID NO:13 with myristoyl attached to the N-terminus as the inhibitor of NTCP, combined with pegylated interferon.
MU teaches the same sequence as instantly elected and claimed SEQ ID NO:13 as its SEQ ID NO:12, and clearly teaches the myristylation of the N-terminal, see for example paragraph 117. This and related acylated peptides are broadly identified and demonstrated to be HBV entry inhibitors as well as HDV entry inhibitors, see Abstract, Fig. 12, and description of Fig. 12, and by virtue of being the same polypeptide sequence has the same inhibition property or properties of what the claimed sequence, so clearly meets the inhibitor of claim 1.
MU, paragraph 280, teaches that its entry inhibitors are effective in chronically infected patients when used in combination with interferon α. Specifically, from paragraph 280, “Apparent indications for clinical applications of HBVpreS-derived lipopeptides are the prevention of not yet established HBV infections (e.g. post exposure prophylaxis, vertical transmission or prevention of reinfection of the liver transplant). However, entry inhibitors are also effective in chronically infected patients, such as in combination with interferon α or inhibitors of the viral RT”, underlined emphasis added.
MU’s SEQ ID NO:12, which is the same as instant elected species is one of MU’s entry inhibitors, which in paragraph 0146 is stated to be a preferred embodiment of P in its formula, see also paragraphs 139-140 and 282.
Also, as to a particular acylated form of SEQ ID NO:12, MU teaches that “Modification by myristoylation is preferred in in vivo and medicinal applications due to its higher safety, e.g. not the adverse effects of the stearoyl group (innate immune response etc),” paragraph 191, see also paragraphs 112 and 188-190.
Thus MU most clearly teaches and suggests the combination of its myristoylated SEQ ID NO:12 inhibitor polypeptide with interferon α, for treating chronically infected patients, which per the publication as a whole clearly includes those patients who have HBV and/or HDV infections, see Abstract, paragraph 1, and multiple other paragraphs which make this clear.
Regarding “wherein the inhibitor is administered at a unit dose of 10 mg per day,” MU, para 264, teaches “In case of an IC50 value of the hydrophobic modified preS-derived peptide used of about 10 nM, a preferred therapeutically effective amount is about 100 µg per kg body weight or in the range of 1 to 5 mg per patient” (underline emphasis added). Considering the first alternative, “about 100 µg per kg body weight,” and as evidenced by Kuk that an adult male average weight is 87.1 kg, see Table 1, page 460, administering at 100 µg per kg body weight for the average adult male weight per Kuk calculates to 8710 µg dosage, or 8.71 mg dosage, which is close to the claimed 10 mg dosage. Daily dosing of such preferred therapeutically effective amount is suggested para 264, albeit this directed to the second alternative, the range of 1 to 5 mg per patient, and also in para 278, which suggests its dosing when considering mice dosage to be provided “daily or every 2 days”. Even assuming, arguendo, that the “about” of the paragraph 264 “preferred therapeutically effective amount is about 100 µg per kg body weight” should be lowered to a percentage below 100 µg per kg body weight, such as ten percent, given the average adult male body weight evidenced by Kuk, the resulting 7.8 mg, also is close to the instantly claimed 10 mg as a “unit dose”.
Per MPEP 2144.05, “… a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.” Here, the prior art calculated administered dose per the first alternative of para 264 when calculated for an average weight human male is close to the claimed unit dose of 10 mg as a daily dosage. As such, a prima facie case of obviousness exists for this dosage.
Additionally, a person of ordinary skill in the art would reasonably interpret the MU para 264 teaching to reasonably apply the about 100 µg per kg body weight administering dosage to also be a once a day administering because the other alternative also was stated to include once a day administering. There is no reasonable basis on the face of the MU teachings to diverge from this administering frequency.
Given that MU demonstrates effectiveness in cell cultures and also mice, and that this dosage is higher than the other stated 2 mg and 5 mg dosages that were stated to be administered daily, there would have been a reasonable expectation of success when administering at this higher dosage, for at least some effect at treating HBV and/or HDV infection(s), as well as any other claimed hepatitis listed in claim 1.
As to the claimed administering of the inhibitor being a unit dose of 10 mg, the 10 mg amount being made obvious based on MU by calculation teaching a close value to this, additionally RemE teaches that a unit-dose packaging of drug products is done routinely, especially in the institutional setting, having advantages including reduced errors because each dose is labelled with the drug identity and strength. Based on such advantage, it would have been obvious to supply the 10 mg daily dose made obvious, as above, in a unit dose in order to reduce errors in an institutional setting. There would have been a reasonable expectation of success given that RemE teaches this is routine.
Having established a prima facie basis for obviousness of administering an inhibitor having an amino acid sequence as set forth in SEQ ID NO:13 at a unit dose of 10 mg per day based on MU, and that MU also teaches administering this with interferon α, MU however does not teach that that the interferon α is pegylated, nor its dosage.
Cooksley clearly teaches that peginterferon α-2a “is superior to conventional interferon α-2a in the treatment of chronic hepatitis C, and reports that it also effectively treats chronic hepatitis B, and in such evaluation also is superior to conventional interferon α-2a” (second paragraph results of Abstract, and that paragraph’s concluding sentence).
When selecting an interferon given the teaching and suggestion in MU to combine this with its entry inhibitor peptides, such as that elected species peptide (SEQ ID NO:12 ~ instant SEQ ID NO:13), it would have been obvious to select a pegylated interferon α-2a given the superior results for two types of chronic hepatitis infections summarized by Cooksley. The rationale is to use a superior form of an interferon, a pegylated interferon, known in the art to be used in treating hepatitis infections.
Regarding “and the pegylated interferon alpha is administered at a unit dose of 180 ug per week,” the Abstract of Cooksley teaches that weekly subcutaneous doses of peginterferon a-2a (40 kDa) of 90, 180 and 270 ug were administered during a Phase II study. This not only brackets, but explicitly identifies the instantly claimed dosage amount, 180 ug per week, and this claim 1 limitation is properly and clearly obvious over this teaching when combined with the other teachings and suggestions set forth in the two applied references, please also see MPEP 2144.05.
The level of ordinary skill in the pertinent art is high, those in the art having advanced degrees in the biological and/or chemical fields and knowledge of viral infections and treatments thereof.
It would have been obvious to combine MU’s SEQ ID NO:13 myristylated at the N-terminal with a pegylated interferon because MU already taught combining its entry inhibitors with interferon α, and Cooksley advanced the art by teaching that administering a pegylated interferon gave superior results for two types of chronic hepatitis infections. The basis is simple substitution of one component with another component that was demonstrated superior for treating the same target disease/condition.
There would have been a reasonable expectation of success given the separate activities of the two active agents, both however having functions that reasonably would reduce the infectivity of HBV (and HDV), and by having different functions at different parts of the viral cycle including liver cell entry (the inhibitor reasonably acting as a decoy to help block HBV cell entry, pegylated interferon stopping the hepatitis virus from replicating itself and providing a boost to the immune system, the latter as evidenced by Everydayhealth page 1), could be expected to reasonably improve therapeutic outcomes, that is, to obtain at least some improvement for some subjects when administered together as a composition or a combination therapy.
Claim 1 therefore would have been obvious.
Because MU teaches acylating its preS1 sequences, including SEQ ID NO:13, at the N-terminus, this providing a hydrophobic moiety, see MU paragraphs 115-120 and table following paragraph 120, claim 6 would have been obvious.
Claims 26 and 27 also would have been obvious because MU per paragraph 191 prefers to acylate with myristoyl, this also being one of the two alternatives of claim 27.
Claim 7 depends from claim 27 and specifies the sequence of instant SEQ ID NO:13 with a myristoyl at the N-terminus. Per MU paragraph 191, and elsewhere MU teaches a myristoyl attached at the N-terminus of the same amino acid sequence, which MU teaches as SEQ ID NO:12, rendering claim 7 obvious.
Claim 9 depends from claim 7 and requires that the pegylated is pegylated interferon alpha 2a or pegylated interferon alpha 2b. Because Cooksley teaches pegylated interferon α-2a, claim 9 would have been obvious on the same bases as claims 1 and 7 combined.
Claim 18 would have been obvious because Cooksley teaches administering its pegylated interferon to treat chronic hepatitis B for 24 weeks, followed by 24 weeks of treatment-free follow-up, and obtained favorable results, Summary, page 298.
Claim 19 would have been obvious because MU clearly teaches intravenous administering of its myristylated SEQ ID NO:12 and other similar peptides, para 257 and claim 31.
In that MU clearly envisions treating humans, see paras 1-6, 10, 11 and 278, and Cooksley did treat human subjects with chronic hepatitis B infections, claim 20 would have been obvious.
Response to Arguments
Applicant's arguments filed 11/20/25, have been fully considered but they are not persuasive.
Applicant page 5 argues against MU suggesting or providing a motivation ‘modifying the reference’ to arrive at the instantly claimed 10 mg dose. However, the examiner, above, has applied additional, previously unapplied teachings from MU to arrive at the modified bases for obviousness necessitated by the claim amendment, which are combined with the Kuk evidentiary reference to provide the average male human subject weight used for calculation.
Applicant also on page 5 argues against MU because “there is no teaching in MU with respect to what the dose of the inhibitor should be or what the dose of the interferon alpha should be when used in combination with each other.” In response to this and other applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Additionally, it matters not that MU states (applicant uses the term “mentions”) in a single passage (applicant uses briefly). To repeat the excerpt from MU from the rejection, “from paragraph 280, “Apparent indications for clinical applications of HBVpreS-derived lipopeptides are the prevention of not yet established HBV infections (e.g. post exposure prophylaxis, vertical transmission or prevention of reinfection of the liver transplant). However, entry inhibitors are also effective in chronically infected patients, such as in combination with interferon α or inhibitors of the viral RT”, underlined emphasis added.” Just as applicant attempts to diminish the importance of this teaching, the examiner counters that it is clear that a chronically infected HBV subject is a subject that, when treated with the claimed inhibitor and pegylated interferon in the manner set forth in claim 1, is encompassed within the scope of claim 1. Accordingly, MU’s underlined statement is relevant to the claimed subject matter, and is not diminished by any alleged briefness of its statement, as applicant asserts. The claimed dosages are addressed elsewhere herein.
With MU having taught the basic addition of interferon alpha as an additional therapeutic agent to be combined with the Myrcludex inhibitor (even if only once it is nonetheless taught), Cooksley as above provides a rationale is to use a superior form of an interferon, a pegylated interferon alpha, known in the art to be used in treating hepatitis infections.
As to Applicant’s argument that there is no teaching of the doses to be used when such therapeutics are used in combination, this is unpersuasive because the Cooksley dose of 180 ug was administered during a Phase II study, and would reasonably be understood by one of ordinary skill in the art to have effectiveness by itself as well as with another therapeutic agent having a different effect on the virus, as is the case for the Myrcludex inhibitor (from the rejection above, “the separate activities of the two active agents, both however having functions that reasonably would reduce the infectivity of HBV (and HDV), and by having different functions at different parts of the viral cycle including liver cell entry (the inhibitor reasonably acting as a decoy to help block HBV cell entry, pegylated interferon stopping the hepatitis virus from replicating itself and providing a boost to the immune system, the latter as evidenced by Everydayhealth page 1)”), could be expected to reasonably improve therapeutic outcomes, that is, to obtain at least some improvement for some subjects when administered together, at doses specifically but separately taught or made prima facie obvious, as a composition or a combination therapy. The examiner also notes that from his reading of the instant specification there is no evidence of having evaluated administering at the instantly claimed combined dosages, so apparently no evidence nor showing of criticality that might overcome the prima facie obviousness rejection for 10 mg dosage (nor any other bases for obviousness of what is claimed), as to the prima facie obviousness rejection for 10 mg dosage in particular please see MPEP 2144.05, in part referring to “In re Dreyfus, 73 F.2d 931, 934, 24 USPQ 52, 55 (CCPA 1934) (the prior art, which taught about 0.7:1 of alkali to water, renders unpatentable a claim that increased the proportion to at least 1:1 because there was no showing that the claimed proportions were critical).”
As to allegation of “picking and choosing”, page 6 of Remarks, what is taught and suggested from the applied Cooksley reference is not choosing one out of hundreds or thousands, as in a prior art reference directed to a large genus, but only 3 dosages from Cooksley for pegylated interferon alpha. Given that the mechanisms for the two agents differ, it would not be unreasonable to use what is taught in Cooksley and taught and suggested in MU as starting dosages for combination therapy dosing, with a very reasonable expectation of success. With regard to MU and the claimed 10 mg daily dosage, as above this is made obvious by MU teaching merely close value(s) when considering the average male weight evidenced by Kuk. Further, based on the respective teachings of the applied references, there has been no “picking and choosing” of disparate elements – MU suggests combining its inhibitor with interferon alpha, and Cooksley clearly demonstrate pegylated interferon alpha’s superiority to the non-pegylated form, for a relevant disease. As to a genus disclosure not rendering every species obvious unless the art specifically points to that species, as to Cooksley the species is clearly identified, and as to MU the obviousness is based on the taught mg/kg body weight dosage value being close to render the 10 mg amount prima facie obvious.
Further in response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Cooksley’s clearly superior results with pegylated interferon versus non-pegylated interferon, even though when focuses on monotherapy, would clearly provide a motivation to one of ordinary skill in the art to substitute this superior pegylated interferon for the non-pegylated interferon of MU when treating subjects for the same viral infections with the MU combination of myristolated SEQ ID NO:13 and an interferon. In light of Cooksley’s teachings of clear superiority of pegylated interferon, not only would there have been a reasonable expectation of success, but one or ordinary skill in the art, in the examiner’s opinion, would be considered behind the progress in the art if that person would not have considered such substitution of pegylated for non-pegylated interferon for any of a number of treatments, including the combined treatment with MU’s Myrcludex inhibitor at the dosage made obvious above.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/JOSEPH FISCHER/Examiner, Art Unit 1658