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 .
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.
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.
Claims 1 – 8 and 11 are rejected under 35 U.S.C. 103 as being obvious over Tzahor et al (WO 2017/072772), hereinafter Tzahor, in view of Wang et al (Wang, Qing-Dong, et al. "Pharmacological possibilities for protection against myocardial reperfusion injury." Cardiovascular research 55.1 (2002): 25-37), hereinafter Wang and Quigley et al (Quigley, P J et al. “Myocardial protection during coronary angioplasty with an autoperfusion balloon catheter in humans.” Circulation vol. 78,5 Pt 1 (1988): 1128-34. doi:10.1161/01.cir.78.5.1128), hereinafter Quigley.
Tzahor teaches a method of treating heart disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an agrin peptide which induces proliferation of cardiomyocytes, wherein the agrin peptide is not part of a fusion polypeptide, is in soluble form, and comprises a laminin G-like 1 domain (G1) and a laminin G-like 2 domain (G2) (see entire document, in particular, Abstract, Summary of Invention, Claims 10 and 13-17). The agrin peptide can have an amino acid sequence of SEQ ID NO: 7, corresponding to SEQ ID NO: 7 of the instant claims (Page 13, Ln. 3-4). The heart disease is an ischemic heart disease (Page 5, Ln. 5 – 6) including acute myocardial infarction, myocardial infarction, or heart failure (Page 23, Ln. 31-32 to Page 24, Ln. 1-7). It is further stated that determination of a therapeutically effective amount is well within the capability of those skilled in the art; and the amount of a composition to be administered will be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc. (Page 28, Ln. 10-11 and Page 29, Ln. 3-5). For example, in the mouse experiments, an agrin peptide was administered at 20 ug/mL following myocardial infarction (Example 1). Additionally, depending on the severity and responsiveness of the condition to be treated, dosing can be of a single or a plurality of administrations, with course of treatment lasting from several days to several weeks or until cure is affected or diminution of the disease state is achieved (Page 28, Ln. 31-32 to Page 29, Ln. 1-2).
Tzahor further teaches that the agrin peptide is administered at 20 μg/mL following myocardial infarction (Page 36, Ln. 15) and may be 50 – 500 amino acids long (Page 13, Ln. 16). Additionally, the agrin peptide comprises a fragment of human agrin in claim 17, which also reads on the full-length human agrin.
Tzahor does not teach that the agrin is administered to the individual in an anterograde intracoronary manner, defined in the specification as injection into the blocked coronary artery with a standard catheter (with the blood flow using an autoperfusion balloon angioplasty catheter) (see Page 18 of Specification).
However, Wang teaches that pharmacological agents delivered locally during percutaneous coronary angioplasty – a standard treatment for ischemic heart disease such as acute myocardial infarction –at the onset of reperfusion can protect against reperfusion injury, leading to limitation of infarct size as well as improved myocardial and endothelial function. In particular, local drug delivery – such as via antegrade (or anterograde) intracoronary administration –can selectively deliver the drug into the target region, achieving a sufficient therapeutic level without affecting the non-ischemic myocardium or producing the off-target systemic effects that can occur with intravenous administration. Further, antegrade intracoronary administration is clinically more feasible than retrograde venous drug delivery (see entire document, in particular, Abstract and Section 2: Pharmacological Agents and Targets, first paragraph).
Quigley further teaches that an autoperfusion balloon catheter, which allows passive myocardial perfusion during inflation through a central lumen and multiple side holes in the shaft proximal and distal to the balloon, significantly reduces ischemic systems and signs during coronary angioplasty, permitting prolonged periods of balloon inflation. Gradual balloon expansion over a more prolonged inflation periods can also result in improved initial angiographic results and lower restenosis rates (see entire document, in particular, Abstract, Introduction, and Discussion: Limitations of Conventional Angioplasty).
It would have been obvious to one of ordinary skill in the art to modify the method of treating an ischemic heart disease such as congestive heart failure, myocardial infarction, or acute myocardial infarction, in a subject with an agrin peptide having an amino acid sequence of SEQ ID NO: 7 as disclosed by Tzhaor such that the agrin peptide is administered in an antegrade intracoronary manner at the onset of reperfusion using an autoperfusion balloon catheter. One of ordinary skill in the art would have been motivated to do so because antegrade intracoronary administration permits the localized delivery of the therapeutic agent to the injured myocardium, achieving a sufficient therapeutic level without affecting the non-ischemic myocardium or producing the off-target systemic effects that can occur with intravenous administration, and is clinically more feasible than retrograde venous drug delivery as taught by Wang. Pharmacological agents delivered at the onset of reperfusion during coronary angioplasty also generally protect against reperfusion injury, limiting infarct size and improving myocardial and endothelial function. Further, an autoperfusion balloon catheter allows passive myocardial perfusion during inflation, significantly reducing ischemic systems and signs during coronary angioplasty and permitting prolonged periods of balloon inflation as taught by Quigley. Lastly, the courts have stated "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum concentration of agrin peptide as well as the frequency and timing of administrations to effectively treat an ischemic heart disease in a subject. Therefore one of ordinary skill in the art would expect that antegrade intracoronary administration of an agrin peptide comprising SEQ ID NO: 7 at the onset of reperfusion to effectively treat an ischemic heart disease such as congestive heart failure, myocardial infarction, or acute myocardial infarction in a subject.
Claims 1-8 and 11 are rejected under 35 U.S.C. 103 as being obvious over Bassat et al (Bassat, Elad et al. “The extracellular matrix protein agrin promotes heart regeneration in mice.” Nature vol. 547,7662 (2017): 179-184. doi:10.1038/nature22978), hereinafter Bassat, in view of Wang et al (Wang, Qing-Dong, et al. "Pharmacological possibilities for protection against myocardial reperfusion injury." Cardiovascular research 55.1 (2002): 25-37), hereinafter Wang, Quigley et al (Quigley, P J et al. “Myocardial protection during coronary angioplasty with an autoperfusion balloon catheter in humans.” Circulation vol. 78,5 Pt 1 (1988): 1128-34. doi:10.1161/01.cir.78.5.1128), hereinafter Quigley, and Tzahor et al, (WO 2017/072772), hereinafter Tzahor, as evidenced by Hoover et al (Hoover et al. The Journal of cell biology vol. 161,5 (2003): 923-32),
Bassat teaches a method of treating myocardial infarction in mice by administering a single injection of agrin to mice at 20 μg/mL following myocardial infarction. Agrin treatment was found to induce cardiomyocyte cell-cycle re-entry in the healthy myocardium adjacent to the infarcted region of both juvenile and adult hearts of mice seven days after myocardial infarction (see entire document, in particular, Abstract, Introduction, Discussion, and “Agrin promotes regeneration after myocardial infarction” section). It is stated that α-Dystroglycan (Dag1) serves as a receptor for agrin (Page 180 of Introduction) and that agrin binding to the dystroglycan induces cardiomyocyte proliferation (Page 182, section “Agrin-DAG1 promotes DGC disassembly and Yap translocation”). While Bassat does not specifically state that the agrin used comprises a laminin G-like 1 domain (G1) and a laminin G-like 2 domain (G2), Hoover teaches that the first two laminin G-like domains (LG1 and LG2) are involved in agrin binding to α-dystroglycan (α-DG) (see “Introduction”, Para. 2), and per Bassat, the binding of agrin to α-dystroglycan (α-DG) mediates cardiomyocyte proliferation. Thus, the agrin used in the treatment of an ischemic heart disease by Bassat comprises the LG1 and LG2 domains in order to bind to α-dystroglycan (α-DG). Further, the agrin would necessarily have to be in soluble form in order to be administered to the subjects.
Bassat does not teach that 1) the agrin is administered to the subject in an anterograde intracoronary manner, defined in the specification as injection into the blocked coronary artery with a standard catheter (with the blood flow using an autoperfusion balloon angioplasty catheter) (see Page 18 of Specification) or 2) the agrin fragment has the amino acid sequence of SEQ ID NO: 7.
However, Wang teaches that pharmacological agents delivered locally during percutaneous coronary angioplasty – a standard treatment for ischemic heart disease such as acute myocardial infarction –at the onset of reperfusion can protect against reperfusion injury, leading to limitation of infarct size as well as improved myocardial and endothelial function. In particular, local drug delivery – such as via antegrade (or anterograde) intracoronary administration –can selectively deliver the drug into the target region, achieving a sufficient therapeutic level without affecting the non-ischemic myocardium or producing the off-target systemic effects that can occur with intravenous administration. Further, antegrade intracoronary administration is clinically more feasible than retrograde venous drug delivery (see entire document, in particular, Abstract and Section 2: Pharmacological Agents and Targets, first paragraph).
Quigley further teaches that an autoperfusion balloon catheter, which allows passive myocardial perfusion during inflation through a central lumen and multiple side holes in the shaft proximal and distal to the balloon, significantly reduces ischemic systems and signs during coronary angioplasty, permitting prolonged periods of balloon inflation. Gradual balloon expansion over a more prolonged inflation periods can also result in improved initial angiographic results and lower restenosis rates (see entire document, in particular, Abstract, Introduction, and Discussion: Limitations of Conventional Angioplasty).
Tzahor teaches a method of treating heart disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an agrin peptide which induces proliferation of cardiomyocytes, wherein the agrin peptide comprises a laminin G-like 1 domain (G1) and a laminin G-like 2 domain (G2) and has the amino acid sequence of SEQ ID NO: 7, corresponding to SEQ ID NO: 7 of the instant claims (see entire document, in particular, Abstract, Summary of Invention, Claims 10 and 13-17, and Page 13, Ln. 3-4). Further, the minimal structure required for an agrin peptide to be soluble is to have or comprise an amino acid sequence of SEQ ID NO: 7 per the instant claims. Thus, the agrin peptide of SEQ ID NO: 7 disclosed by Tzhaor is necessarily soluble in form.
It would have been obvious to one of ordinary skill in the art to modify the method of treating myocardial infarction (a type of ischemic heart disease) in a subject with an agrin peptide as disclosed by Bassat such that the agrin peptide comprises the amino acid sequence of SEQ ID NO: 7 and is administered in an antegrade intracoronary manner at the onset of reperfusion using an autoperfusion balloon catheter. One of ordinary skill in the art would have been motivated to do so because antegrade intracoronary administration permits the localized delivery of the therapeutic agent to the injured myocardium, achieving a sufficient therapeutic level without affecting the non-ischemic myocardium or producing the off-target systemic effects that can occur with intravenous administration, and is clinically more feasible than retrograde venous drug delivery as taught by Wang. Pharmacological agents delivered at the onset of reperfusion during coronary angioplasty also generally protect against reperfusion injury, limiting infarct size and improving myocardial and endothelial function. Further, an autoperfusion balloon catheter allows passive myocardial perfusion during inflation, significantly reducing ischemic systems and signs during coronary angioplasty and permitting prolonged periods of balloon inflation as taught by Quigley. Additionally, it would have been obvious to artisans to substitute the agrin peptide disclosed by Bassat with the agrin peptide disclosed by Tzhaor since they have the same function and can be used for the same purpose. An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Lastly, the courts have stated "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum concentration of agrin peptide as well as the frequency and timing of administrations to effectively treat an ischemic heart disease in a subject. Therefore one of ordinary skill in the art would expect that antegrade intracoronary administration of an agrin peptide comprising SEQ ID NO: 7 at the onset of reperfusion to effectively treat an ischemic heart disease such as myocardial infarction in a subject.
Claims 1-8 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Smith et al (US20100095387A1), hereinafter Smith, in view of Wang et al (Wang, Qing-Dong, et al. "Pharmacological possibilities for protection against myocardial reperfusion injury." Cardiovascular research 55.1 (2002): 25-37), hereinafter Wang, Quigley et al (Quigley, P J et al. “Myocardial protection during coronary angioplasty with an autoperfusion balloon catheter in humans.” Circulation vol. 78,5 Pt 1 (1988): 1128-34. doi:10.1161/01.cir.78.5.1128), hereinafter Quigley, Chancellor et al ( US20160274126A1), hereinafter Chancellor, and Nattel et al (Nattel, Stanley et al. “Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation.” Physiological reviews vol. 87,2 (2007): 425-56. doi:10.1152/physrev.00014.2006), hereinafter Nattel, as evidenced by Quaye (Quaye, E. “Congestive Heart Failure: A Primer for Patient Awareness”, Cardiology Advisor, (2024)).
Smith teaches methods of treating an ion pump-associated disorder in an individual comprising administering an agrin fragment to the individual, wherein the ion-pump associated disorder is congestive heart failure and the individual is a human (see entire document, in particular, Abstract, Summary of Invention, Claims, Para. 0010, and Claims 12-35). Examples of agrin fragments disclosed include the 95 kDa mouse agrin fragments C-Ag95z8 and C-Ag95z0 comprising the laminin-like G1 and G2 domains (Figure 2, Example 1, and Para. 0211). The agrin peptides can be used for human subjects as long as they are biocompatible (Para. 0176). Congestive heart failure is a chronic, or lifelong condition, as evidenced by Quaye; and, per the claims, chronic heart failure, is a type of ischemic heart disease. Thus, the methods of Smith apply to treatment of an ischemic heart disease, specifically congestive heart failure, which is a chronic condition.
Smith does not teach that 1) the agrin is administered to the individual in an anterograde intracoronary manner, defined in the specification as injection into the blocked coronary artery with a standard catheter (with the blood flow using an autoperfusion balloon angioplasty catheter) (see Page 18 of Specification) or 2) the agrin fragment has the amino acid sequence of SEQ ID NO: 7.
However, Wang teaches that pharmacological agents delivered locally during percutaneous coronary angioplasty – a standard treatment for ischemic heart disease such as acute myocardial infarction –at the onset of reperfusion can protect against reperfusion injury, leading to limitation of infarct size as well as improved myocardial and endothelial function. In particular, local drug delivery – such as via antegrade (or anterograde) intracoronary administration –can selectively deliver the drug into the target region, achieving a sufficient therapeutic level without affecting the non-ischemic myocardium or producing the off-target systemic effects that can occur with intravenous administration. Further, antegrade intracoronary administration is clinically more feasible than retrograde venous drug delivery (see entire document, in particular, Abstract and Section 2: Pharmacological Agents and Targets, first paragraph).
Quigley further teaches that an autoperfusion balloon catheter, which allows passive myocardial perfusion during inflation through a central lumen and multiple side holes in the shaft proximal and distal to the balloon, significantly reduces ischemic systems and signs during coronary angioplasty, permitting prolonged periods of balloon inflation. Gradual balloon expansion over a more prolonged inflation periods can also result in improved initial angiographic results and lower restenosis rates (see entire document, in particular, Abstract, Introduction, and Discussion: Limitations of Conventional Angioplasty).
Chancellor further teaches human agrin having the amino acid sequence of SEQ ID NO: 10, fully comprising SEQ ID NO: 7 of the instant claims (see entire document, in particular, Sequence Listing and Para. 0029). Further, the minimal structure required for an agrin peptide to be soluble is to comprise an amino acid sequence of SEQ ID NO: 7 per the instant claims. Thus, the agrin of SEQ ID NO: 10 disclosed by Chancellor is necessarily in a soluble form.
Nattel further teaches that, in addition to congestive heart failure, myocardial infarction (including acute myocardial infarction) is associated with arrhythmogenic remodeling, or alterations in ion channel and transporter properties. In particular, acute myocardial infarction causes longer term (remodeling) changes over days to weeks, as well as important very early (within minutes to hours) functionally based ion-channel abnormalities caused by intracellular acidosis, K+ loss, and membrane breakdown (see entire document, in particular, Abstract, Introduction, “Remodeling of Ionic Currents Associated with Cardiac Disease: Myocardial Infarction”). Thus, acute myocardial infarction can be considered an ion pump associated disorder disclosed by Smith; and, per the claims, acute myocardial infarction, is a type of ischemic heart disease.
It would have been obvious to one of ordinary skill in the art to modify the method of treating an ion-pump disorder such as congestive heart failure in a subject with an agrin peptide as disclosed by Smith such that the agrin peptide comprises the amino acid sequence of SEQ ID NO: 7 and is administered in an antegrade intracoronary manner at the onset of reperfusion using an autoperfusion balloon catheter. One of ordinary skill in the art would have been motivated to do so because antegrade intracoronary administration permits the localized delivery of the therapeutic agent to the injured myocardium, achieving a sufficient therapeutic level without affecting the non-ischemic myocardium or producing the off-target systemic effects that can occur with intravenous administration, and is clinically more feasible than retrograde venous drug delivery as taught by Wang. Pharmacological agents delivered at the onset of reperfusion during coronary angioplasty also generally protect against reperfusion injury, limiting infarct size and improving myocardial and endothelial function. Further, an autoperfusion balloon catheter allows passive myocardial perfusion during inflation, significantly reducing ischemic systems and signs during coronary angioplasty and permitting prolonged periods of balloon inflation as taught by Quigley. Additionally, it would have been obvious to artisans to use human agrin peptides to treat human subjects and to substitute the agrin peptides disclosed by Smith with the agrin peptide disclosed by Chancellor since they have the same function and can be used for the same purpose. An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Given that the methods of Smith can treat ion pump associated disorders, and acute myocardial infarction is associated with alterations in ion channels and transporter properties; the methods of Smith in view of Wang, Quigley, and Chancellor can also be used to treat acute myocardial infarction in a subject. Lastly, the courts have stated "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum concentration of agrin peptide as well as the frequency and timing of administrations to effectively treat an ischemic heart disease in a subject. Therefore one of ordinary skill in the art would expect that antegrade intracoronary administration of an agrin peptide comprising SEQ ID NO: 7 at the onset of reperfusion to effectively treat an ischemic heart disease such as congestive heart failure, myocardial infarction, or acute myocardial infarction in a subject.
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.
Claims 1-8 and 11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 11786640B2 in view of Wang et al (Wang, Qing-Dong, et al. "Pharmacological possibilities for protection against myocardial reperfusion injury." Cardiovascular research 55.1 (2002): 25-37), hereinafter Wang, Quigley et al (Quigley, P J et al. “Myocardial protection during coronary angioplasty with an autoperfusion balloon catheter in humans.” Circulation vol. 78,5 Pt 1 (1988): 1128-34. doi:10.1161/01.cir.78.5.1128), hereinafter Quigley, and Chancellor et al ( US20160274126A1), hereinafter Chancellor.
The issued claims recite a method of treating heart disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an agrin peptide which induces cardiomyocyte proliferation, wherein agrin is not part of a fusion polypeptide and is 80 – 110 kDa and wherein the heart disease is an ischemic heart disease such as acute myocardial infarction (AMI), myocardial infarction (MI), or heart failure (issued claims 7, 13-15, and 21). Additionally, the agrin peptide can comprise a fragment of human agrin (issued claims 10 and 18).The ability of agrin to induce cardiomyocyte proliferation is dependent on its binding to dystroglycan (Bassat et al, Page 11, Ln. 17 – 22 and Example 6) (WO 2017/072772), and it is known that the first two laminin G-like domains (G1 and G2) of agrin bind to α-dystroglycan (α-DG(Hoover et al, see entire document, in particular “Introduction”, Para. 2) (Hoover et al. The Journal of cell biology vol. 161,5 (2003): 923-32). Thus, the agrin peptide of the issued claims necessarily comprises the G1 and G2 domains.
The issued claims do not recite that 1) the agrin is administered to the subject in an anterograde intracoronary manner, defined in the specification as injection into the blocked coronary artery with a standard catheter (with the blood flow using an autoperfusion balloon angioplasty catheter) (see Page 18 of Specification); 2) the agrin fragment comprises the amino acid sequence of SEQ ID NO: 7, or 3) agrin is administered at a specific dosage or dosage frequency.
However, Wang teaches that pharmacological agents delivered locally during percutaneous coronary angioplasty – a standard treatment for ischemic heart disease such as acute myocardial infarction –at the onset of reperfusion can protect against reperfusion injury, leading to limitation of infarct size as well as improved myocardial and endothelial function. In particular, local drug delivery – such as via antegrade (or anterograde) intracoronary administration –can selectively deliver the drug into the target region, achieving a sufficient therapeutic level without affecting the non-ischemic myocardium or producing the off-target systemic effects that can occur with intravenous administration. Further, antegrade intracoronary administration is clinically more feasible than retrograde venous drug delivery (see entire document, in particular, Abstract and Section 2: Pharmacological Agents and Targets, first paragraph).
Quigley further teaches that an autoperfusion balloon catheter, which allows passive myocardial perfusion during inflation through a central lumen and multiple side holes in the shaft proximal and distal to the balloon, significantly reduces ischemic systems and signs during coronary angioplasty, permitting prolonged periods of balloon inflation. Gradual balloon expansion over a more prolonged inflation periods can also result in improved initial angiographic results and lower restenosis rates (see entire document, in particular, Abstract, Introduction, and Discussion: Limitations of Conventional Angioplasty).
Chancellor further teaches human agrin having the amino acid sequence of SEQ ID NO: 10, fully comprising SEQ ID NO: 7 of the instant claims (see entire document, in particular, Sequence Listing and Para. 0029). Further, the minimal structure required for an agrin peptide to be soluble is to comprise an amino acid sequence of SEQ ID NO: 7 per the instant claims. Thus, the agrin of SEQ ID NO: 10 disclosed by Chancellor is necessarily in a soluble form.
It would have been obvious to one of ordinary skill in the art to modify the method of the issued claims such that the agrin peptide comprises the amino acid sequence of SEQ ID NO: 7 and is administered in an antegrade intracoronary manner at the onset of reperfusion using an autoperfusion balloon catheter. One of ordinary skill in the art would have been motivated to do so because antegrade intracoronary administration permits the localized delivery of the therapeutic agent to the injured myocardium, achieving a sufficient therapeutic level without affecting the non-ischemic myocardium or producing the off-target systemic effects that can occur with intravenous administration, and is clinically more feasible than retrograde venous drug delivery as taught by Wang. Pharmacological agents delivered at the onset of reperfusion during coronary angioplasty also generally protect against reperfusion injury, limiting infarct size and improving myocardial and endothelial function. Further, an autoperfusion balloon catheter allows passive myocardial perfusion during inflation, significantly reducing ischemic systems and signs during coronary angioplasty and permitting prolonged periods of balloon inflation as taught by Quigley. Additionally, it would have been obvious to artisans to substitute the agrin peptides disclosed by the issued claims with the agrin peptide disclosed by Chancellor comprising SEQ ID NO: 7 since they have the same function and can be used for the same purpose. An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Lastly, the courts have stated "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum concentration of agrin peptide as well as the frequency and timing of administrations to effectively treat an ischemic heart disease in a subject. Therefore one of ordinary skill in the art would expect that antegrade intracoronary administration of an agrin peptide comprising SEQ ID NO: 7 at the onset of reperfusion to effectively treat an ischemic heart disease such as congestive heart failure, myocardial infarction, or acute myocardial infarction in a subject.
Claims 1-8 and 11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 10,589,132, and in view of Wang et al (Wang, Qing-Dong, et al. "Pharmacological possibilities for protection against myocardial reperfusion injury." Cardiovascular research 55.1 (2002): 25-37), hereinafter Wang, Quigley et al (Quigley, P J et al. “Myocardial protection during coronary angioplasty with an autoperfusion balloon catheter in humans.” Circulation vol. 78,5 Pt 1 (1988): 1128-34. doi:10.1161/01.cir.78.5.1128), hereinafter Quigley, and Chancellor et al ( US20160274126A1), hereinafter Chancellor; and Awada et al (Awada, Hassan K et al. “Towards comprehensive cardiac repair and regeneration after myocardial infarction: Aspects to consider and proteins to deliver.” Biomaterials vol. 82 (2016): 94-112. doi:10.1016/j.biomaterials.2015.12.025), hereinafter Awada.
The issued claims recite a method of treating heart disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an agrin peptide comprising a laminin G-like 1 domain (G1) and a laminin G-like 2 domain (G2) (issued claim 9), wherein the agrin is peptide is not part of a fusion polypeptide and wherein heart disease is an ischemic heart disease (issued claim 10).
The issued claims do not recite that 1) the agrin is administered to the subject in an anterograde intracoronary manner, defined in the specification as injection into the blocked coronary artery with a standard catheter (with the blood flow using an autoperfusion balloon angioplasty catheter) (see Page 18 of Specification); 2) the agrin fragment comprises the amino acid sequence of SEQ ID NO: 7, 3) agrin is administered at a specific dosage or dosage frequency; or 4) the ischemic heart disease is chronic heart failure, myocardial infarction, or acute myocardial infarction.
However, Wang teaches that pharmacological agents delivered locally during percutaneous coronary angioplasty – a standard treatment for ischemic heart disease such as acute myocardial infarction –at the onset of reperfusion can protect against reperfusion injury, leading to limitation of infarct size as well as improved myocardial and endothelial function. In particular, local drug delivery – such as via antegrade (or anterograde) intracoronary administration –can selectively deliver the drug into the target region, achieving a sufficient therapeutic level without affecting the non-ischemic myocardium or producing the off-target systemic effects that can occur with intravenous administration. Further, antegrade intracoronary administration is clinically more feasible than retrograde venous drug delivery (see entire document, in particular, Abstract and Section 2: Pharmacological Agents and Targets, first paragraph).
Quigley further teaches that an autoperfusion balloon catheter, which allows passive myocardial perfusion during inflation through a central lumen and multiple side holes in the shaft proximal and distal to the balloon, significantly reduces ischemic systems and signs during coronary angioplasty, permitting prolonged periods of balloon inflation. Gradual balloon expansion over a more prolonged inflation periods can also result in improved initial angiographic results and lower restenosis rates (see entire document, in particular, Abstract, Introduction, and Discussion: Limitations of Conventional Angioplasty).
Chancellor further teaches human agrin having the amino acid sequence of SEQ ID NO: 10, fully comprising SEQ ID NO: 7 of the instant claims (see entire document, in particular, Sequence Listing and Para. 0029). Further, the minimal structure required for an agrin peptide to be soluble is to comprise an amino acid sequence of SEQ ID NO: 7 per the instant claims. Thus, the agrin of SEQ ID NO: 10 disclosed by Chancellor is necessarily in a soluble form.
Awada further teaches that ischemic heart disease is a leading cause of death worldwide. Myocardial infarction, in particular, occurs as a result of an occlusion in one of the two main coronary arteries branching into the heart walls due to coronary atherosclerosis or thrombosis, leading to heart muscle damage and progression to chronic heart failure as a result of the ischemia (see entire document, in particular, Abstract and Introduction).
It would have been obvious to one of ordinary skill in the art to modify the method of the issued claims such that the 1) agrin peptide comprises the amino acid sequence of SEQ ID NO: 7 and is administered in an antegrade intracoronary manner at the onset of reperfusion using an autoperfusion balloon catheter and 2) the ischemic heart disease is myocardial infarction or heart failure. One of ordinary skill in the art would have been motivated to do so because antegrade intracoronary administration permits the localized delivery of the therapeutic agent to the injured myocardium, achieving a sufficient therapeutic level without affecting the non-ischemic myocardium or producing the off-target systemic effects that can occur with intravenous administration, and is clinically more feasible than retrograde venous drug delivery as taught by Wang. Pharmacological agents delivered at the onset of reperfusion during coronary angioplasty also generally protect against reperfusion injury, limiting infarct size and improving myocardial and endothelial function. Further, an autoperfusion balloon catheter allows passive myocardial perfusion during inflation, significantly reducing ischemic systems and signs during coronary angioplasty and permitting prolonged periods of balloon inflation as taught by Quigley. Moreover, since the method of the issued claims can treat ischemic heart disease; and myocardial infarction and chronic heart failure are considered ischemic heart diseases as taught by Awada; then, artisans would be motivated to use the methods of the issued claims to treat myocardial infarction or chronic heart failure in a subject specifically. Additionally, it would have been obvious to artisans to substitute the agrin peptides disclosed by the issued claims with the agrin peptide disclosed by Chancellor since they have the same function and can be used for the same purpose. An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Lastly, the courts have stated "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum concentration of agrin peptide as well as the frequency and timing of administrations to effectively treat an ischemic heart disease in a subject. Therefore one of ordinary skill in the art would expect that antegrade intracoronary administration of an agrin peptide comprising SEQ ID NO: 7 at the onset of reperfusion to effectively treat an ischemic heart disease such as congestive heart failure or myocardial infarction in a subject.
Response to Arguments
Applicant's arguments filed 08/06/2025 have been fully considered but they are not persuasive.
With respect to the rejection made under 35 USC 103, Applicant makes the following points:
It is per se improper for the Examiner to "stitch together an obviousness finding from discrete portions of prior art references ...." MPEP § 2143.01(IV). Without the present claims and specification as a guide, the Examiner would have had no reason to select anterograde intracoronary administration as the claimed route of administration from agrin.
None of the primary references teach administering agrin in an anterograde intracoronary manner, as claimed.
The secondary references Wang and Quigley have anything to do with agrin and thus do not cure the deficiencies of the primary reference.
Wang focuses on small molecule drugs with vastly different mechanisms of action compared to agrin. Moreover, while "antegrade intracoronary administration" is mentioned once (see p. 26), Wang fails to provide any teaching or suggestion of any specific drugs administered via this route. Instead, every example of administration actually discuss within Wang is retrograde.
Quigley teaches that a balloon catheter can allow for antegrade perfusion of blood during angioplasty; it has nothing to do with administration of any pharmaceutical compound, much less agrin.
Hoover, Chancellor, and Nattel are likewise devoid of any discussion relevant to this element of the claims.
To properly sustain an assertion of prima facie obviousness, the Examiner must show that a person of ordinary skill would (not merely could) administer a human agrin peptide or a fragment thereof in "an anterograde intracoronary manner." A determination that Agrin allegedly could be administered this way because other, unrelated drugs were administered by this route is not sufficient.
In sum, Applicant asserts that the primary references fail to teach administering agrin in an anterograde intracoronary manner and the secondary references-at best-teach that "antegrade intracoronary administration" existed, but fail to provide any specific suggestions about what drugs could or should be administered via this route. In other words, this record established nothing more than agrin and "antegrade intracoronary administration" were separately known.
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 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). Further, 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, the rejection does not merely suggest that the cited references disclose that one could administer a therapeutic agent via anterograde intracoronary delivery. Rather, the references teach that anterograde intracoronary administration permits localized delivery of a therapeutic agent to the injured myocardium, achieving sufficient therapeutic levels without affecting non-ischemic myocardium or producing off-target effects, and is clinically more feasible than retrograde venous drug delivery. These teachings would have provided a clear motivation for a person of ordinary skill in the art to employ anterograde intracoronary administration in the treatment of an ischemic heart disease, particularly where localized myocardial delivery is desired.
Further, disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971) (MPEP 2123). Even if the examples of Wang focus on small molecule drugs, that does not detract from the advantages of anterograde intracoronary administration of a therapeutic agent; and these advantages apply regardless of the physiochemical nature of the therapeutic agent. Indeed, the prior art teaches that not only small molecules but also peptides/proteins, have been delivered via intracoronary routes to achieve localized cardiac effects. For example, Schumacher teaches that intracoronary administration of the growth factor FGF-1 promotes revascularization in the ischemic myocardium (see entire document, in particular, Abstract). Thus, anterograde intracoronary delivery of other therapeutic agents besides small molecule drugs (e.g. peptides/proteins) for local treatment of injured myocardium was certainly not unheard of as Applicant seems to suggest. Quigley additionally teaches the advantages of using an autoperfusion balloon catheter to prolong balloon inflation and reduce ischemic events during coronary angioplasty, which allows delivery of therapeutic agents via the anterograde route.
Chancellor teaches human agrin comprising the amino acid sequence of SEQ ID NO: 7. Hoover teaches that the first two laminin G-like domains (LG1 and LG2) are involved in agrin binding to α-dystroglycan (α-DG), which mediates cardiomyocyte proliferation. Nattel teaches that myocardial infarction – an ischemic heart disease recited in the claims- involves ion-channel abnormalities. Thus, myocardial infarction can be a type of ion-pump associated disorder taught by Smith, establishing the nexus between these two references. As such, Hoover, Chancellor, and Nattel are all relevant to the claim limitations contrary to Applicant’s assertion.
In view of the above, the rejections under 35 USC 103 are maintained.
The amendments to claims 1 and 11 overcome the rejections made under 35 USC 112(a) written description and enablement as well as 35 USC 112(d).
Conclusion
No claims are 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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/LIA E TAYLOR/Examiner, Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641