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 . 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 (i.e., changing from AIA to pre-AIA ) 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.
Election/Restrictions
Applicants elected group I (conjugates) and a peptide moiety of formula I or Ia conjugated to a bile acid or bile acid multimer without traverse in the reply filed on 19 May, 2025.
Claims Status
Claims 1, 4-6, 8-10, 12-18, 20, and 21 are pending.
Claims 4-6, 9, 12-18, 20, and 21 have been withdrawn from consideration due to an election/restriction requirement.
Withdrawn Objections
The objection to the drawings due to the lack of SEQ ID numbers is hereby withdrawn due to amendment.
Withdrawn Rejections
The rejection of claims 1-3, 8, and 10 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph due to uncertainty as to what is a NTCP substrate moiety is hereby withdrawn due to amendment.
The rejection of claim 2 i under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite due to uncertainty as to the cutoff between a hydrophobic and a non-hydrophobic moiety is hereby withdrawn due to amendment.
The rejection of claim 3 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite due to lack of antecedent support for hydrophobic modifications is hereby withdrawn due to amendment.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 7, 8, 10, and 19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1, and claims dependent on it, has a limit on the number of amino acids that can be in the sequence, but also allows for modifications on the N and C termini that can be polypeptides. However, the cutoff between the peptide of the structure, and the modifications (which can include peptides) is in the mind of the person designing the construct. In other words, the cutoff between the peptide (with limitations on the number of amino acids) and the modifications is arbitrary.
response to applicant’s arguments
Applicants argue that they have canceled claim 2, and that, while the limitations have been moved to claim 1, they have also limited the hydrophobic moiety.
Applicant's arguments filed 3 Oct, 2025 have been fully considered but they are not persuasive.
Applicants claim that they have canceled claim 2, overcoming this rejection. However, the limitations of the claim have been moved to claim 1. Moving an issue to another claim does not typically avoid the issue.
Applicants argue that they have defined the hydrophobic moiety in the claim. There are two problems with this argument. First, the Markush group that applicants have added includes cholesterol derivatives and isoprene derivatives. Applicants have not defined derivative, so the dictionary definition (Merriam Webster online), “a substance that can be made from another substance” is used. That is broad enough to include peptides. The second is that the hydrophobic moiety is limited to the N-terminus, the C-terminus merely requires “a moiety that protects from degradation.” This is broad enough to include additional polypeptide sequences, such as one that would protect from an exopeptidase.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 7, 8, 10, and 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Alexandrov (EP 3392267, cited by applicants).
Alexandrov discusses peptides that inhibit NTCP (abstract). An embodiment of the invention comprises a peptide NPLGFXP, with X being any amino acid, but preferably F or L, more preferably F (paragraph 15). This can have an additional 4 or more AA segment on the N-terminus (paragraph 15), and 1 or more amino acids at the C-terminus (paragraph 16). The peptide can be any length between 7 and 119 amino acids in length (paragraph 18). The peptide can be modified with a hydrophobic moiety at or around the N-terminus (paragraph 25) and can be modified at the C-terminus to protect the peptide from degradation (paragraph 28). Note that this matches formula I of applicants. The hydrophobic moiety can be a bile salt (p23, line 58), which is a cholesterol derivative. Note that this is applicant’s elected species, and anticipates claims 1, 7, 8, and 19. The formulation may be a pharmaceutical formulation comprising acceptable carriers or excipients (paragraph 35), anticipating claim 10.
response to applicant’s arguments
Applicants argue that the bile acid is not described in the reference as a second domain, as required by the claim, and that the peptide of the reference does not match what applicants have claimed.
Applicant's arguments filed 3 Oct, 2025 have been fully considered but they are not persuasive.
Applicants are arguing that the reference does not state that the bile acid is a second domain. The fact that applicants are using different language than the reference to describe the same thing does not change the structure of the embodiment of the prior art.
Applicants state that the sequence of the reference does not match applicant’s claimed sequence. Applicants have not pointed out the differences between the sequence of the prior art and applicant’s claims. Without such an explanation, this argument is merely a statement of disagreement.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created 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 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 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 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); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
first rejection
Claims 1, 7, 8, 10, and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 8, and 16 of U.S. Patent No. 9,562,076 in view of Armstrong et al (J. Lipid. Res. (1982) 23 p70-80).
Competing claim 1 specifies a peptide with a hydrophobic moiety attached to the N-terminus and a C-terminal modification that protects from degradation. Competing claim 2 specifies SEQ ID 11, a peptide of 47 AAs comprising the sequence NPLGFFP. Note that this corresponds to formula I of applicants, if some of the amino acids are considered protection against degradation or hydrophobic moieties. Competing claim 8 requires a hydrophobic moiety selected from a group comprising cholesterol derivatives. Competing claim 16 requires a method of use in vivo, which requires a pharmaceutical formulation. Note that the extra amino acids beyond the 7 AA motif explicitly claimed by applicants have every feature that applicants have stated is required for being an NTCP substrate moiety, so this anticipates examined claims 1 and 2.
The difference between the competing claims and the remaining examined claims is that the competing claims do not discuss an NTCP substrate.
Armstrong et al discuss the hydrophobic-hydrophilic balance of bile salts (title). These have a hydrophobic face, and a hydrophilic face with one or more hydroxyl groups and a carboxylate group, which can be used for conjugation (fig 1, p71, 1st column, top of page). A person of skill in the art would understand that, once the carboxylate is conjugated, it will not have a charge, making the species hydrophobic.
Therefore, it would be obvious to use a bile acid salt as a hydrophobic moiety of the competing claims, as a simple substitution of one known element (the hydrophobic moiety of the competing claims) with another (the hydrophobic bile acid salt) yielding expected results (a hydrophobic construct). As the competing claims discuss cholesterol derivatives, a genus that includes bile acids, an artisan in this field would attempt this modification with a reasonable expectation of success.
response to applicant’s arguments
Applicants argue that Armstrong et al does not teach that the bile acid salt is a NTCP substrate, and has nothing to do with applicant’s claimed subject matter, that the rejection is based on hindsight reasoning, and that the logic of the rejection does not lead to applicant’s claimed invention.
Applicant's arguments filed 3 Oct, 2025 have been fully considered but they are not persuasive.
Applicants argue that Armstrong et al does not teach that the bile acid salt is an NTCP substrate. It is not clear how this overcomes the rejection; the name of the protein indicates that bile acids are a substrate.
Applicants argue that Armstrong et al has nothing to do with applicant’s claimed subject matter. This is an argument of non-analogous art. A reference is analogous if the reference is from the same field of endeavors as the claimed invention, or if the reference is reasonable pertinent to the problem faced by the inventor. A person attempting to improve the activity of the competing claims would reasonably investigate different hydrophobic moieties, making Armstrong et al reasonably pertinent to the problem.
Applicants state that the logic of the rejection does not lead to applicant’s invention. There is no explanation of the differences between where the rejection leads and applicant’s claims, making this nothing more than a statement of disagreement.
second rejection
Claims 1, 7, 8, 10, and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9, and 11 of U.S. Patent No.9,868,768 in view of Poupon et al (N.E. J. Med. (1994) 330 p1342-1347).
Competing claim 1 describes a hydrophobically modified peptide, comprising SEQ ID 1 or a truncated version comprising at least 10 AAs, that is acylated on the N-terminus, has a C-terminal modification that protects from degradation, and is conjugated to a Markush group of compounds, including drugs. Competing claim 9 specifies that the sequence be selected from a Markush group of sequences, including SEQ ID 38, an 11 AA sequence comprising NPLGFFP. Competing claim 11 specifies a pharmaceutical formulation. Note that the extra amino acids beyond the 7 AA motif explicitly claimed by applicants have every feature that applicants have stated is required for being an NTCP substrate moiety, so this anticipates examined claims 1, 2, and 10.
The difference between the competing claims and the examined claims is that the competing claims do not specify a bile acid.
Poupon et al describes a clinical trial to treat primary biliary cirrhosis with ursodiol (a bile acid) (title). This slowed the progression of the disease and reduced the need for liver transplant (abstract).
Therefore, it would be obvious to attach the ursodiol of Poupon et al to the peptide of the competing claims, as an embodiment of the genus described by the competing claims. As attachment chemistry is well established, an artisan in this field would attempt this modification with a reasonable expectation of success.
response to applicant’s arguments
Applicants argue that Poupon et al does not provide motivation to conjugate the bile acid to the sequence of the competing claims
Applicant's arguments filed 3 Oct, 2025 have been fully considered but they are not persuasive.
Applicants argue that the secondary reference does not provide a motivation to combine. The rationale to combine is that the secondary reference describes a species (ursodiol) of the genus of the competing claims (drugs that treat the liver) – essentially a substitution of one element for another yielding predicted results.
third rejection
Claims 1, 7, 8, 10, and 19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9, and 10 of Application No. 18/330,135 (US 20240123025) in view of Paumgartner et al (Hepatology (2002) 36 p525-531).
Competing claim 1 describes a method of preventing or treating a liver disease selected from a Markush group of conditions mostly involving cholestasis, comprising administering a compound comprising SEQ ID 1 modified on both the N-terminus and C-terminus by additional amino acids (totaling at least 11). Competing claim 9 specifies N-terminal myristoylation and C-terminal amide. Note that this meets the limitations of formula I of the examined claims. Competing claim 10 specifies attachment of a Markush group of compounds, that includes drugs.
The difference between the competing claims and the examined claims is that the competing claims do not mention an NTCP substrate.
Paumgartner et al discuss using ursodeoxycholic acid in cholestatic liver disease (title). This has proven beneficial in a number of cholestatic disorders (abstract).
Therefore, it would be obvious to attach the bile acid of Paumgartner et al to the peptide of the competing claims, as this drug is used to treat the same disorders. As the competing claims explicitly discuss conjugating drugs to the peptide, an artisan in this field would attempt this modification with a reasonable expectation of success.
response to applicant’s arguments
Applicants argue that they will take appropriate action once the claims have otherwise been indicated as allowable. However, until the rejection is overcome, it will remain valid.
fourth rejection
Claims 1, 7, 8, 10, and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 6 of U.S. Patent No. 10,413,585.
Competing claim 1 describes a method of treating cardiovascular disease (which requires a pharmaceutical formulation), comprising administering any one of a handful of sequences comprising NPLGFFP, modified with a hydrophobic moiety on the C-terminus and myristylation on the N-terminus. Note that, while these sequences are longer than the number of amino acids allowed by the examined claims, the excess amino acids can be considered part of the hydrophobic moiety of the N-terminus or the preserving moiety of the C-terminus. Competing claim 9 specifies conjugation to a Markush group of compounds, including bile salts.
response to applicant’s arguments
Applicants argue that the hydrophobic moiety has been limited to exclude additional amino acids.
Applicant's arguments filed 3 Oct, 2025 have been fully considered but they are not persuasive.
There are two issues with this argument. First, the hydrophobic moiety includes cholesterol derivatives and isoprene derivatives; genera that are broad enough to include peptide sequences. Second, applicants have made no argument about adding additional amino acids on the C-terminus, as part of the sequence to reduce degradation.
fifth rejection
Claims 1, 7, 8, 10, and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, and 6 of U.S. Patent No.11,401,304 in view of Poupon et al (N.E. J. Med. (1994) 330 p1342-1347).
Competing claim 1 describes cyclic peptides comprising NPLGFFP with a hydrophobic modification. Competing claim 5 specifies a conjugation of a Markush group of compounds, including drugs, while competing claim 6 specifies a pharmaceutical formulation.
The difference between the competing claims and the examined claims is that the competing claims do not specify a bile acid.
Poupon et al describes a clinical trial to treat primary biliary cirrhosis with ursodiol (a bile acid) (title). This slowed the progression of the disease and reduced the need for liver transplant (abstract).
Therefore, it would be obvious to attach the ursodiol of Poupon et al to the peptide of the competing claims, as an embodiment of the genus described by the competing claims. As attachment chemistry is well established, an artisan in this field would attempt this modification with a reasonable expectation of success.
response to applicant’s arguments
Applicants argue that Poupon et al does not provide motivation to conjugate the bile acid to the sequence of the competing claims
Applicant's arguments filed 3 Oct, 2025 have been fully considered but they are not persuasive.
Applicants argue that the secondary reference does not provide a motivation to combine. The rationale to combine is that the secondary reference describes a species (ursodiol) of the genus of the competing claims (drugs that treat the liver).
Conclusion
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRED REYNOLDS whose telephone number is (571)270-7214. The examiner can normally be reached M-Th 9-3:30.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658
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