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.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 16 March, 2026 has been entered.
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, 12-15, 17, 18, 20, and 21 are pending.
Claims 1 and 4 have been amended.
Claims 6, 8, 9, 12-15, 18, 20, and 21 have been withdrawn from consideration due to an election/restriction requirement.
Withdrawn Rejections
The rejection of claim(s) 1, 7, 8, 10, and 19 under 35 U.S.C. 102(a)(1) as being anticipated by Alexandrov (EP 3392267, cited by applicants) is hereby withdrawn in favor of a new rejection below.
The rejection of claims 1, 7, 8, 10, and 19 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 (1982) 23 p70-80) is hereby withdrawn due to amendment.
The rejection of claims 1, 7, 8, 10, and 19 on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 6 of U.S. Patent No. 10,413,585 is hereby withdrawn due to amendment.
Maintained/Modified Rejections
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, 4, 5, 10, and 17 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 removed all Markush entries that can be additional amino acids.
Applicant's arguments filed 16 March, 2026 have been fully considered but they are not persuasive.
The C-terminal addition can be a d-amino acid, a modified amino acid (which can be a peptide), and a cyclic amino acid. In addition, withdrawn claim 6 explicitly discusses adding additional amino acids, which presumably would not be included in n or m.
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, 4, and 10 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) and Irby et al (Mol. Pharmaceut. (2017) 14 p1325-1338).
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 selected from a Markush group comprising amides and albumin (modified amino acid), 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 or the same hydrophobic moieties as applicants.
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). Note the structure has a carboxylate and two hydroxyl groups; the only attachment that will be reproducible is via the carboxylate, as the two hydroxyl groups will both react if they are used for conjugation.
Irby et al discusses lipid-drug conjugates (title). This gives numerous advantages, including reduced toxicity and enhanced loading into drug carriers (p1325, 1st column, 1st paragraph). These can be fatty acids, such as the competing claims, or steroids, glycerides, or phospholipids (fig 1, p1326, 1st column, top of page). A number of steroids are discussed, including cholesterol, ursodeoxycholic acid (the same as the ursodiol of Poupon et al), and lithocholic acid, another bile acid. This reference discusses hydrophobic moieties.
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.
Furthermore, it would be obvious to use one of the hydrophobic moieties of Irby et al for the fatty acids of the competing claims as a substitution of one known element (the fatty acids of the competing claims) for another (the lipids of Irby et al) yielding expected results. As Irby et al discusses a genus that includes the fatty acids of the competing claims which are used for the same purpose as the other moieties, an artisan in this field would attempt this modification with a reasonable expectation of success.
response to applicant’s arguments
Applicants state that the claim amendments have overcome this rejection.
Applicant's arguments filed 16 March, 2026 have been fully considered but they are not persuasive.
The rejection has been modified to take those amendments into account.
second rejection
Claims 1, 4, and 10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, and 6 of U.S. Patent No. 12,370,237 in view of Irby et al (Mol. Pharmaceut. (2017) 14 p1325-1338).
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), a C-terminal amide, and an N-terminal acylation. Competing claim 2 specifies that the sequence transports a number of compounds into the liver, including bile salts and sulfonated bile salts. Competing claim 6 requires conjugation to a Markush group of compounds, including drugs. Note that the combination of these two claims renders obvious attaching the bile acids via a carboxylate or sulfonate, as that is the easiest way to attach them.
The difference between the competing claims and the examined claims is that the competing claims have a different hydrophobic moiety attached to the N-terminus.
Irby et al discusses lipid-drug conjugates (title). This gives numerous advantages, including reduced toxicity and enhanced loading into drug carriers (p1325, 1st column, 1st paragraph). These can be fatty acids, such as the competing claims, or steroids, glycerides, or phospholipids (fig 1, p1326, 1st column, top of page). A number of steroids are discussed, including cholesterol, ursodeoxycholic acid (the same as the ursodiol of Poupon et al), and lithocholic acid, another bile acid. This reference discusses hydrophobic moieties.
Therefore, it would be obvious to use one of the hydrophobic moieties of Irby et al for the fatty acids of the competing claims as a substitution of one known element (the fatty acids of the competing claims) for another (the lipids of Irby et al) yielding expected results. As Irby et al discusses a genus that includes the fatty acids of the competing claims which are used for the same purpose as the other moieties, an artisan in this field would attempt this modification with a reasonable expectation of success.
response to applicant’s arguments
Applicants state that the claim amendments have overcome this rejection.
Applicant's arguments filed 16 March, 2026 have been fully considered but they are not persuasive.
The rejection has been modified to take those amendments into account.
third rejection
Claims 1, 4, and 10 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). Note the structure has a carboxylate and two hydroxyl groups; the only attachment that will be reproducible is via the carboxylate, as the two hydroxyl groups will both react if they are used for conjugation.
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 state that the claim amendments have overcome this rejection.
Applicant's arguments filed 16 March, 2026 have been fully considered but they are not persuasive.
The rejection has been modified to take those amendments into account.
New Rejections
Claim Rejections - 35 USC § 112(b)
The basis for rejections under this statute was given above, and will not be repeated here.
Claims 1, 4, 5, 10, and 17 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 allows for a hydrophilic moiety “glycane.” It is not clear what this is; this is not a word in the dictionary (Merriam Webster online dictionary):
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, nor did a search in Google find a meaning for this word in English.
Claim Rejections - 35 USC § 103
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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 4, 5, 10, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Alexandrov (EP 3392267, previously cited).
Alexandrov discusses peptides that inhibit NTCP to treat primary biliary cirrhosis, among other disorders (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). This sequence can be positions 2-21 of the HBV pre-S1 sequence (paragraph 72), which is SEQ ID 2 of applicants. The peptide can be modified at the C-terminus to protect the peptide from degradation, with such moieties as d-amino acids, cyclic amino acids, modified amino acids, and polymers such as PEG (paragraph 28). One or more hydrophobic moieties, such as cholesterol, phospholipids, glycolipids, glycerol esters, steroids, and ceramids can be attached to the N-terminus (preferably) or near the N-terminus (paragraphs 88 and 89). A hydrophobic moiety in these positions can be a bile salt (p23, line 58), which is a substrate of the NTCP (paragraph 45). Note that this is applicant’s elected species. The hydrophobic moieties can be attached via carbamate, amide, ether, or disulfide bonds (p24, line 3). Formulations of these compounds dissolved in sterile aqueous solutions, such as saline or Ringer’s solution (paragraph 184).
While this reference discusses every limitation of applicant’s claims, reconstruction of applicant’s elected species requires selection from different lists, which makes obviousness a better fit than anticipation.
Alexandrov teaches SEQ ID 2 of applicants as a peptide that can be used to treat liver disorders. This peptide can have a hydrophobic moiety selected from a list almost identical to applicants attached to the N-terminus, and a hydrophilic moiety almost identical to applicants attached to the C-terminus. A bile acid salt (an NTCP substrate) is also attached near the N-terminus by a group comprising an amide, which requires a carboxylate. And the only practical reaction site is the Asn side chain. Thus, the reference renders obvious claims 1, 4, and 5.
Alexandrov mentions formulations with a pharmaceutically acceptable carrier/excipient, rendering obvious claim 10.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Honda et al (Hepatology (2013) 57 p1931-1941) teaches that ursodeoxycholic acid is the first line medication for treatment of primary biliary cirrhosis, the disorder described by Alexandrov.
Muller-Schiffmann et al (Biodrugs (2012) 26(1) p21-31) and Domalaon et al (Clin. Microbiol. Rev. (2018) 31(2) e00077-17) both discuss the advantages of covalently binding two drugs to treat the same disorder.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melissa Fisher can be reached at 571-270-7430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658
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