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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 4/2/26 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Claims 11-14 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species, there being no allowable generic or linking claim.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 1,6-7,9,18-19, 26-27, 30 are pending.
Claims 2-5, 8, 10-17, 20-25, 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(Claims 11-14 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species, there being no allowable generic or linking claim.)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 1,6-7,9,18-19, 26-27, 30 have been examined.
Claims 1,6-7,9,18-19, 26-27, 30 are rejected.
Priority
The instant application, filed 03/23/2021 and having 2 RCE-type filings 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.
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 1,6-7,9,18-19, 26-27, 30 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 Grabowski et al., Liver International, ISSN 1478-3223, 2011, pages 1395-1405, Wedemeyer et al., N Engl J Med 2011;364:322-31, 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, previously provided), as evidenced by Kuk et al., Am J Epidemiol 2009;170:456–463 (Kuk, previously provided).
Claim 1 is directed to a method of treating a HDV infection in a human subject in need thereof comprising administering to the human 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, para 11 which states, “Furthermore, to date there exists no effective therapy for HDV infection, a satellite virusoid utilizing HBV envelope proteins for the entry into hepatocytes (15, 17, 20). There is a need in the art to provide effective therapies against HDV infection, para 13 which states, “It is a further objective of the present invention to provide methods and means for the inhibition, prevention and/or treatment of HDV infection and HDV-related diseases,” see also paras 21-23, 156, 159, 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, which per the clear teachings are used to treat HDV infection.
MU, paragraph 181, 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. Please note, importantly, that elsewhere in MU MU teaches its entry inhibitors to be effective for treating HDV infections, such as Title, paras 2, 132, 154, 156.
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 HDV infections, see Abstract, paragraph 1, and multiple other paragraphs, including those referenced above, 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 or HDV infection(s).
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.
Grabowski teaching treating HDV infections with pegylated interferon alpha and reports that “HDV-specific cytokine responses declined during pegylated (PEG)-IFNa therapy and patterns of changes were associated with the treatment response,” Abstract. Grabowski references the study of Wedemeyer, from which blood samples were taken, and Wedemeyer teaches a dosage to human patients of 180 ug of peginterferon alpha2a weekly, see Methods, page 322. This was effective to provide “sustained HDV RNA clearance in about one quarter of patients with HDV infection” page 322 (for which the background states, as to chronic infection with HBV and HDV “There is no currently approved treatment”). 180 ug weekly is the same as the instantly claimed dosage.
When selecting an interferon given the teaching and suggestion in MU to combine this with its entry inhibitor peptides, including for HDV infection treatment, 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 as taught by Grabowski and Wedemeyer which respectively gave both favorable cytokine and in-patient results and improvements. The rationale is to use a superior form of an interferon, a pegylated interferon, shown in the art to be used in treating HDV infections, to obtain an improved therapeutic effectiveness.
Regarding “and the pegylated interferon alpha is administered at a unit dose of 180 ug per week,” Wedemeyer 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 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 Grabowski and Wedemeyer advanced the art by teaching that administering a pegylated interferon gave favorable changes in cytokines and patient outcomes for treating HDV. The basis is simple substitution of one component with another component that was demonstrated superior for treating an infection of interest, here HDV infection.
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 HDV (and for the inhibitor also HBV, which is required to complete the virus packaging of HBV), 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 HDV (and also HBV) cell entry, pegylated interferon clearly shown to be effective for alteration of cytokine responses to HDV and sustained HDV RNA clearance in a portion of evaluated HDV patients, 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 to treat HDV infection in a human subject.
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 Grabowski and also Wedemeyer teach 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 Wedemeyer teaches administering its pegylated interferon to treat chronic hepatitis D for 48 weeks, see first page.
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 Wedemeyer did treat human subjects having HDV infections, these subjects having to have met criteria that included having compensated liver disease and having been positive for anti-HDV antibodies for at least 3 months, claim 30 would have been obvious. See pages 323-324.
Response to Arguments
Applicant's arguments filed 4/2/26, have been fully considered but they are not persuasive.
The page 5 quoted passage from MU refers to entry inhibitors in combination with interferon alpha a. Elsewhere in MU, as set forth in the modified rejection above, now focusing on treating HDV infection as claimed, it is clear that MU teaches its entry inhibitors are for treating HDV as well as HBV infections (and please note that HDV is a satellite virus and requires HBV, see Grabowski and Wedemeyer).
The examiner has considered the data, including the entire Appendix A provided 10/11/24, and assertions of “surprising technical effect”, pages 6-10, however is not persuaded of such effect/result. First, what applicant sets forth in arguments/Remarks 4/2/26 does not fully align with the Appendix A data, at least because the chart corresponding to slide 12 in Appendix A refers to “Undetectable HDV RNA or >= 2-log10 IU/mL Decline” whereas applicant’s arguments refer only to undetectable. Interpreting as best understood, slide 12 teaches 13% undetectable in the PEG-IFNa group, and 34% undetectable in the PEG-IFNa plus 10 mg BLV group. Given that Wedemeyer’s results with only pegylated interferon resulted in “sustained HDV RNA clearance” in about one quarter of patients with HDV infection, page 322 Conclusions, the results set forth by applicant as best understood by the examiner, weighing the evidence at hand, do not demonstrate a surprising technical effect, nor unexpected results given that one of ordinary skill in the art would reasonably expect improvements over PEG-IFNa alone when also administering an inhibitor known to affect both HBV and its satellite virus HDV.
As to arguments on page 8 regarding neither MU nor Cooksley, Cooksley is no longer applied, and data is not required to make an obviousness rejection. As above, based on the examiner’s understanding and comparing applicant data to Wedemeyer data, the examiner is not persuaded of unexpected synergistic effect.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH FISCHER whose telephone number is (571)270-7925. The examiner can normally be reached on Monday to Friday, 9:00 AM to 5:00 PM, however noting that the examiner will not normally be working on Wednesday-Friday and on Monday/Tuesday on alternating weeks, but will promptly answer messages upon his return to work.
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/JOSEPH FISCHER/Primary Examiner, Art Unit 1658
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