DETAILED CORRESPONDENCE
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 35-50 are pending in the application and are being examined on the merits.
Applicant’s amendment to the claims, filed January 20, 2026, is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Applicant’s amendment to the specification, filed January 20, 2026, is acknowledged.
Applicant’s amendment to the drawing figures, filed January 20, 2026, is acknowledged.
Applicant’s remarks filed January 20, 2026 in response to the non-final rejection filed July 18, 2025 are acknowledged and have been fully considered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Specification/Informalities
The objections to the specification are withdrawn in view of applicant’s amendment to the specification.
Drawings
The objections to the drawing figures are withdrawn in view of applicant’s amendment to the drawings.
Claim Objections
The objections to claims 35-50 are withdrawn in view of applicant’s amendment to the claims and upon further consideration.
Claim Rejections - 35 USC § 112(b)
The rejection of claims 35-50 under 35 U.S.C. 112(b) is withdrawn in view of applicant’s amendment to the claims.
Claims 49 and 50 are newly rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
As amended, claims 49 and 50 recite the limitation "the polypeptide.” While claims 49 and 50 depend from claims 48 and 35, respectively, which recite “a peptide compound,” “a carrier peptide,” and “a peptide capable of interacting with an intracellular domain of connexin43,” there is insufficient antecedent basis for the limitation “the polypeptide” in claims 49 and 50.
Claim Rejections - 35 USC § 103
Claims 35-43 and 48-50 are rejected under 35 U.S.C. 103 as being unpatentable over Schulz et al. (Pharmacology and Therapeutics 153:90-106, 2015; citation 448 of the IDS filed January 5, 2023; hereafter “Schulz”) in view of Nicholson et al. (WO 2014/129914 A1; cited on Form PTO-892 filed July 18, 2025; hereafter “Nicholson”) and Krissansen, G. (US 2013/0210749 A1; cited on Form PTO-892 filed July 18, 2025; hereafter “Krissansen”).
As amended, the claims are drawn to a method of treating acute or chronic ischemia in a subject comprising administering to the subject a therapeutically effective amount of a peptide compound comprising:
(a) a carrier peptide derived from the X-protein of the Hepatitis B virus and
(b) a peptide capable of interacting with an intracellular domain of connexin43 (Cx43).
Schulz summarizes the existing evidence for the role of Connexin 43 (Cx43) in irreversible injury of heart and brain tissues following ischemia/reperfusion, which highlights Cx43 as an emerging drug target for cardio- and neuroprotection (p. 92, column 2, bottom). Discussing pharmacological modulation of Cx43-formed channels, Schulz teaches the available pharmacological agents inhibiting hemichannels include small molecule inhibitors, however, these lack specificity and substantial interest has been directed to peptides as agents with better selectivity potential (p. 94, column 2). Schulz teaches a peptide referred to as “Gap19,” which is a Cx43 mimetic peptide having the amino acid sequence of KQIEIKKFK (identical to instant SEQ ID NO: 3) that specifically blocks Cx43 hemichannels (p. 91, Fig. 1; p. 95, column 2). Table 2 of Schulz shows that Gap19 decreased ischemia of the heart (p. 97). Discussing myocardial ischemia/reperfusion injury and cardioprotection, Schulz teaches cardiomyocyte swelling caused by simulated ischemia/reoxygenation was blocked by Gap19 and as a consequence, cardiomyocyte survival was increased (p. 98, column 2, bottom).
Nicholson teaches that vascular integrity of retinal vessels was shown to be compromised following ischemia-reperfusion, while delivery of a Cx43 mimetic peptide via a single injection significantly reduced vascular leak (p. 9, lines 9-16; p. 19, lines 22-28). Nicholson teaches vascular leak appears to be a common feature of acute injury and chronic diseases (p. 18, lines 2-3). Nicholson teaches Gap19 as a connexin-specific agent and as an agent to protect, restore and/or maintain vasculature (p. 62, top).
In view of the teachings of Schulz and Nicholson, it would have been obvious to one of ordinary skill in the art before the effective filing date to administer Gap19 for the treatment of acute or chronic ischemia. One would have been motivated and would have expected success to do this because Schulz teaches the Cx43 mimetic peptide, Gap19, decreased ischemia of the heart and blocked cardiomyocyte swelling caused by simulated ischemia, and Nicholson teaches vascular leak as a common feature of acute injury and chronic diseases, teaches a Cx43 mimetic peptide significantly reduced vascular leak following ischemia-reperfusion, and teaches Gap19 as a connexin-specific agent and as an agent to protect, restore and/or maintain vasculature.
Schulz further teaches Gap19 can be linked to a membrane translocation motif to improve/facilitate cell entry and access to the Cx43 target (p. 96, column 1), however, Schulz and Nicholson do not teach or suggest a peptide derived from the X-protein of Hepatitis virus B including the peptide LCLRPV as a membrane translocation motif.
Krissansen teaches peptides derived from the X-protein of the hepatitis B virus that are cell permeable and can be used for delivery of therapeutic compounds to subjects, the peptides having a number of advantages (paragraph [0118]). Krissansen teaches the peptide LCLRPVG (paragraph [0014]) and fusing the peptide LCLRPVG to a heterologous amino acid sequence (claim 66). Krissansen teaches connecting the carrier peptide to the N-terminus of the compound (paragraph [0168]) and teaches a glycine linker to separate the peptide LCLRPVG and a fusion partner (paragraph [0294]). Krissansen teaches the peptides may be D-amino acids (paragraph [0142]). The amino acid sequence of LCLRPVG with D-enantiomer amino acids comprises SEQ ID NO: 2 of this application.
In view of Schulz and Krissansen, it would have been obvious to one of ordinary skill in the art to fuse the peptide lclrpvG (glycine does not have L- and D-enantiomers) with a glycine linker to the N-terminus of Gap19, which would have the sequence lclrpvGGKQIEIKKFK. One would have been motivated and would have expected success to do this because Schulz teaches Gap19 can be linked to a membrane translocation motif and Krissansen teaches the peptide lclrpvG with advantageous properties as a cell permeable peptide (i.e., translocation motif) and teaches fusing the peptide lclrpvG to the N-terminus of a heterologous amino acid sequence with an intervening glycine linker for delivery of therapeutic compounds into a cell.
Therefore, the invention of claims 35-43 and 48-50 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claims 44-47 are rejected under 35 U.S.C. 103 as being unpatentable over Schulz in view of Nicholson and Krissansen as applied to claims 35-43 and 48-50 above, and further in view of Kane et al. (Therapy 2:709-716, 2005; cited on Form PTO-892 filed July 18, 2025; hereafter “Kane”).
Claims 44-47 are drawn to, respectively, a method according to claim 36, further comprising administration of a therapeutically effective amount of an anticoagulant or a clot breakdown compound;
a method according to claim 44, wherein the anticoagulant or a clot breakdown compound comprises a tissue plasminogen activator or a recombinant tissue plasminogen activator;
a method according to claim 45, wherein the tissue plasminogen activator is selected from the group consisting of alteplase, reteplase, tenecteplase and desmoteplase; and
a method according to claim 44, wherein administration of the anticoagulant or a clot breakdown compound occurs prior to reperfusion, during reperfusion and/or after reperfusion.
The combination of Schulz, Nicholson, and Krissansen does not teach or suggest administering a therapeutically effect amount of an anticoagulant or a clot breakdown compound as recited in claims 44-47.
Kane teaches a recombinant tissue plasminogen activator referred to as Alteplase (p. 710, column 1, bottom), which is used as a thrombolytic therapy for acute ischemic stroke (p. 709, column 2, middle). Kane teaches the idea behind thrombolytic therapy is that, by dissolving the clot occluding the cerebral artery, ischemic brain tissue is reperfused quickly and teaches early reperfusion should decrease the volume of brain tissue damaged by ischemia and, hence, lead to less neurologic impairment and less disability (p. 709, column 1, bottom).
In view of the teachings of Kane, it would have been obvious to one of ordinary skill in the art before the effective filing date to administer Gap19 in combination with Alteplase for the treatment of acute ischemia. One would have been motivated and would have expected success to do this because each of Schulz and Nicholson taught and/or suggested Gap19 for treating acute ischemia, Kane taught Alteplase for treating acute ischemia, and it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose (MPEP 2144.06.I).
Therefore, the invention of claims 44-47 would have been obvious to one of ordinary skill in the art before the effective filing date.
RESPONSE TO REMARKS: Applicant addresses each of Schulz, Nicholson, and Krissansen individually and argues the diffuse focus of these references does not render obvious the claimed invention. According to applicant, an indication of non-obviousness is that these very old publications never led anyone to the claimed invention and if the invention was obviousness, someone else would have long ago made the claimed invention.
Applicant’s arguments are not found persuasive. In response to 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 MPEP 2145.IV. Prior art references may be relied upon for all that they would have reasonably suggested to those of ordinary skill in the art (MPEP 2123) and contrary to applicant’s position, in view of the combined teachings of the cited prior art, the claimed invention would have been prima facie obvious before the effective fling date.
In response to applicant's argument based upon the age of the references, contentions that the cited prior art is old are not persuasive of nonobviousness absent a showing that the prior art tried and failed to solve the same problem notwithstanding its presumed knowledge of the references. See MPEP 2145.VIII.
For these reasons, it is the examiner’s position that the claimed invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claim Rejections - 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 35-43 and 48-50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5, 6, and 27-30 of U.S. Patent No. 11,466,069 B2 (cited on Form PTO-892 filed July 18, 2025) in view of Schulz and Nicholson.
Regarding instant claims 35-43 and 48-50, claim 1 of the patent recites a polypeptide construct comprising:
(a) a targeting carrier peptide derived from the X-protein of the Hepatitis B virus and
(b) a peptide capable of interacting with an intracellular domain of connexin43 (Cx43);
claim 2 of the patent recites (in relevant part) wherein the targeting carrier peptide comprises or consists of SEQ ID NO: 2, which is identical to SEQ ID NO: 2 of this application;
claim 5 of the patent recites (in relevant part) wherein the peptide capable of interacting with an intracellular domain of Cx43 is SEQ ID NO: 3, which is identical to SEQ ID NO: 3 of this application;
claim 6 of the patent recites (in relevant part) wherein the targeting carrier peptide is connected by a linker to the peptide capable of interacting with an intracellular domain of Cx43; optionally wherein the linker is a glycine linker;
claim 27 of the patent recites a method for targeting delivery of a peptide capable of interacting with an intracellular domain of connexin43 to hypoxic cells in a subject, comprising administering to the subject the polypeptide construct of claim 1,
claim 28 of the patent recites wherein the subject has a disease or disorder associated with hypoxia,
claim 29 of the patent recites (in relevant part) wherein the disease or disorder is cardiovascular disease, and
claim 30 of the patent recites (in relevant part) wherein the cardiovascular disease is cardiac ischemia.
The claims of the patent do not recite “acute” or “chronic” with respect to “ischemia.”
Schulz summarizes the existing evidence for the role of Connexin 43 (Cx43) in irreversible injury of heart and brain tissues following ischemia/reperfusion, which highlights Cx43 as an emerging drug target for cardio- and neuroprotection (p. 92, column 2, bottom). Discussing pharmacological modulation of Cx43-formed channels, Schulz teaches the available pharmacological agents inhibiting hemichannels include small molecule inhibitors, however, these lack specificity and substantial interest has been directed to peptides as agents with better selectivity potential (p. 94, column 2). Schulz teaches a peptide referred to as “Gap19,” which is a Cx43 mimetic peptide having the amino acid sequence of KQIEIKKFK (identical to SEQ ID NO: 3 of the patent and this application) that specifically blocks Cx43 hemichannels (p. 91, Fig. 1; p. 95, column 2). Table 2 of Schulz shows that Gap19 decreased ischemia of the heart (p. 97). Discussing myocardial ischemia/reperfusion injury and cardioprotection, Schulz teaches cardiomyocyte swelling caused by simulated ischemia/reoxygenation was blocked by Gap19 and as a consequence, cardiomyocyte survival was increased (p. 98, column 2, bottom).
Nicholson teaches that vascular integrity of retinal vessels was shown to be compromised following ischemia-reperfusion, while delivery of a Cx43 mimetic peptide via a single injection significantly reduced vascular leak (p. 9, lines 9-16; p. 19, lines 22-28). Nicholson teaches vascular leak appears to be a common feature of acute injury and chronic diseases (p. 18, lines 2-3). Nicholson teaches Gap19 as a connexin-specific agent and as an agent to protect, restore and/or maintain vasculature (p. 62, top).
In view of the teachings of Schulz and Nicholson, it would have been obvious to one of ordinary skill in the art before the effective filing date to administer the polypeptide construct of the claims of the patent for the treatment of acute or chronic ischemia. One would have been motivated and would have expected success to do this because the claims of the patent recite administering the polypeptide construct to a subject having cardiac ischemia, Schulz teaches the Cx43 mimetic peptide, Gap19, decreased ischemia of the heart and blocked cardiomyocyte swelling caused by simulated ischemia, and Nicholson teaches vascular leak as a common feature of acute injury and chronic diseases, teaches a Cx43 mimetic peptide significantly reduced vascular leak following ischemia-reperfusion, and teaches Gap19 as a connexin-specific agent and as an agent to protect, restore and/or maintain vasculature.
Therefore, claims 35-43 and 48-50 are unpatentable over the claims of the patent in view of Schulz and Nicholson.
Claims 44-47 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5, 6, and 27-30 of U.S. Patent No. 11,466,069 B2 (cited on Form PTO-892 filed July 18, 2025) in view of Schulz and Nicholson as applied to claims 35-43 and 48-50 above, and further in view of Kane.
The claims of the patent do not recite and Schulz and Nicholson do not teach or suggest administering a therapeutically effect amount of an anticoagulant or a clot breakdown compound as recited in claims 44-47.
Kane teaches a recombinant tissue plasminogen activator referred to as Alteplase (p. 710, column 1, bottom), which is used as a thrombolytic therapy for acute ischemic stroke (p. 709, column 2, middle). Kane teaches the idea behind thrombolytic therapy is that, by dissolving the clot occluding the cerebral artery, ischemic brain tissue is reperfused quickly and teaches early reperfusion should decrease the volume of brain tissue damaged by ischemia and, hence, lead to less neurologic impairment and less disability (p. 709, column 1, bottom).
In view of the teachings of Kane, it would have been obvious to one of ordinary skill in the art before the effective filing date to administer the polypeptide construct in combination with Alteplase for the treatment of acute ischemia. One would have been motivated and would have expected success to do this because the claims of the patent recite administering the polypeptide construct to a subject having cardiac ischemia, each of Schulz and Nicholson taught and/or suggested Gap19 for treating acute ischemia, Kane taught Alteplase for treating acute ischemia, and it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose (MPEP 2144.06.I).
Therefore, claims 44-47 are unpatentable over the claims of the patent in view of Schulz, Nicholson, and Kane.
RESPONSE TO REMARKS: Applicant requests the rejections are held in abeyance until an indication of allowable subject matter. Applicant’s request is acknowledged.
Conclusion
Status of the claims:
Claims 35-50 are pending.
Claims 35-50 are rejected.
No claim is in condition for allowance.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID J STEADMAN whose telephone number is (571)272-0942. The examiner can normally be reached Monday to Friday, 7:30 AM to 4:00 PM.
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/David Steadman/Primary Examiner, Art Unit 1656