DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2 Applicant's amendment, filed on 11/04/2025, is acknowledged.
3. The numbering of claims is not in accordance with 37 CFR 1.126 which requires the original numbering of the claims to be preserved throughout the prosecution. When claims are canceled, the remaining claims must not be renumbered. When new claims are presented, they must be numbered consecutively beginning with the number next following the highest numbered claims previously presented (whether entered or not).
There are two claims numbered 60. Misnumbered claims 60- 69 been renumbered as claims 61-70 according to 37 CFR 1.126.
4. Claims 57-70 are pending.
5. Applicant’s election with traverse the following species: aa1-137 for Map44 fragment, SEQ ID NO: 1-6 specific targeting moiety and Annexin IV as the target, filed on 11/04/2025, is acknowledged.
Applicant’s traversal is on the grounds that there will be no additional burden to search all species. This is not found persuasive because the specific antibodies/polypeptides combination provides many possible combinations that are recognized divergent subject matter. In addition, the different antibodies are distinct because their structures are different and are therefore capable of separate manufacture, use and sale, and searches of all species would place an undue burden upon the examiner due to the distinct and divergent subject matter of each species. Further, a prior art search also requires a literature search. It is an undue burden for the examiner to search more than one invention.
The requirement is still deemed proper and is therefore made FINAL.
6. Claims 61-66 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.
7. Claims 57-59 and 67-70 are under examination as they read on the following species: aa1-137 for Map44 fragment, SEQ ID NO: 1-6 specific targeting moiety and Annexin IV as the target.
8. The following is a quotation of 35 U.S.C. 112(b) (Pre AIA , 35 U.S.C. 112, second paragraph):
(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.
9. Claims 59-60 are rejected under 35 U.S.C. 112(b), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
A) Claims 59-60 are indefinite in the recitation of "monoclonal antibody B4" because its characteristics are not known. The use of "monoclonal antibody B4" as the sole means of identifying the claimed antibody and hybridoma renders the claim indefinite because "monoclonal antibody B4" is merely a laboratory designation which does not clearly define the claimed product, since different laboratories may use the same laboratory designation s to define completely distinct hybridomas.
10. The following is a quotation of 35 U.S.C. 112(a) (Pre-AIA 35 U.S.C. 112, first paragraph):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
11. Claims 59-60 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as containing subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
It is apparent that the hybridoma that produce the B4 antibody is required to practice the claimed invention. As a required element, it must be known and readily available to the public or obtainable by a repeatable method set forth in the specification. If it is not so obtainable or available, the enablement requirements of 35 USC 112, a deposit of the hybridoma, which produces this antibody, may satisfy first paragraph. See 37 CFR 1.801-1.809.
If the deposit has been made under the terms of the Budapest Treaty, an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature, stating that the hybridoma has been deposited under the Budapest Treaty and that the hybridoma will be irrevocably and without restriction or condition released to the public upon the issuance of a patent would satisfy the deposit requirement made herein. See 37 CFR 1.808. Further, the record must be clear that the deposit will be maintained in a public depository for a period of 30 years after the date of deposit or 5 years after the last request for a sample or for the enforceable life of the patent whichever is longer. See 37 CFR 1.806. If the deposit has not been made under the Budapest treaty, then an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature must be made, stating that the deposit has been made at an acceptable depository and that the criteria set forth in 37 CFR 1.801-1.809, have been met.
If the deposit was made after the effective filing date of the application for a patent in the United States, a verified statement is required from a person in a position to corroborate that the hybridoma described in the specification as filed are the same as that deposited in the depository. Corroboration may take the form of a showing of a chain of custody from applicant to the depository coupled with corroboration that the deposit is identical to the biological material described in the specification and in the applicant’s possession at the time the application was filed.
Further, amendment of the specification to disclose the date of deposit and the complete name and address of the depository (ATCC.10801 University Boulevard, Manassas, VA 20110-2209) is required as set forth in 37 C.F.R. 1.809(d).
12. 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.
13. Claims 57-59 and 67-70 are rejected under 35 U.S.C. 103 as being unpatentable over Arkinson et al (Abstract # 29, Molecular Immunology 47 (2010) 2198–2294) OR WO2014116880 (Rohrer) or US20110014270A1 (Holers) in view of US 20120122107 (Thiel).
Arkinson et al teaches that previous studies indicate a pivotal role for pathogenic natural IgM antibodies in mediating complement activation following ischemia and reperfusion. Arkinson et al previously reported that IgM mAbs specific for annexin IV (B4 mAb) or a subset of phospholipids (C2 mAb) recognize neoepitopes exposed on post-ischemic endothelium, and initiate complement activation in models of intestinal, cerebral and hepatic ischemia reperfusion injury (IRI). Arkinson et al teach that hearts transplanted into antibody-deficient Rag1−/− recipient mice are protected from cold and warm IRI, and that reconstitution with either B4 or C2 mAb (but not control IgM) restores myocardial IRI in the transplanted hearts. Further, in B4 mAb treated recipient mice, IgM co-localizes with C3 on myocytes and vascular structures within the heart. Given these findings, Arkinson prepared a single chain Ab (scFv) from variable domains derived from the B4 hybridoma for therapeutic characterization as a targeting vehicle. When administered immediately postreperfusion in an allograft transplant model (C3H to B6), B4scFv co-localized with an endothelial marker in hearts harvested 6 hrs post-transplantation. Soluble Crry was then recombinantly linked to B4scFv, and the scFv-Crry construct characterized in the same allograft model. When administered immediately after reperfusion, scFv-Crry (0.2 mg) resulted in a significant reduction in myocardial IRI as evidenced by decreased histopathological damage and serum lactate dehydrogenase levels at 48 h post-transplantation. In addition, scFv-Crry reduced C3 deposition, inflammatory cell infiltration and inflammatory cytokine generation (TNF-alpha, IL-1 beta, and MCP-1) compared to control treated mice. In conclusion, Arkinson et al describe a novel strategy to target complement inhibition to post-ischemic endothelium. The specificity of this targeting approach offers potential advantages over other types of targeted complement inhibition, and the targeting vehicle itself has the potential to block the binding of pathogenic IgM to post-ischemic endothelium.
The `880 publication teaches and claims constructs comprising: (a) an antibody or a fragment thereof, wherein the antibody or a fragment thereof specifically binds to Annexin IV; and (b) a complement modulator or a detectable moiety, wherein the antibody or fragment there of comprises: (i) a light chain variable domain comprising a sequence of claimed and published SEQ ID NO: 1 or 7, a sequence of SEQ ID NO:2 or 8, or a sequence of claimed and published SEQ ID NO:3 or 9; and/or (ii) heavy chain variable domain comprising a sequence of claimed and published SEQ ID NO:4 or 10, a sequence of SEQ ID NO:5 or 11, or a sequence of claimed and published SEQ ID NO:6 or 12, wherein the antibody or fragment there of comprises: (i) a light chain variable domain comprising a sequence of claimed and published SEQ ID NO: l or 7; (ii) a light chain variable domain comprising a sequence of SEQ ID NO:2 or 8; and (iii) a light chain variable domain comprising a sequence of claimed and published SEQ ID NO:3 or 9, wherein the antibody or fragment there of comprises: (i) heavy chain variable domain comprising a sequence of claimed and published SEQ ID NO:4 or 10; (ii) heavy chain variable domain comprising a sequence of claimed and published SEQ ID NO:5 or 11; and (iii) heavy chain variable domain comprising a sequence of claimed and published SEQ ID NO:6 or 12, wherein the antibody or fragment thereof binds to the same epitope as monoclonal antibody B4 (comprising the claimed SEQ ID Nos) the Annexin IV is present on the surface of a cell in an individual that is in or adjacent to a tissue undergoing or is at risk of undergoing tissue injury (see claims 27-56).
Further, the `880 publication teaches methods of inhibiting complement-mediated inflammation in a tissue having non-ischemic injury in an individual, comprising administering to the individual an effective amount of a composition comprising a construct, wherein the construct comprises (a) an antibody or a fragment thereof, wherein the antibody or a fragment thereof specifically binds to Annexin IV or a phospholipid; and (b) a complement inhibitor. Claims 1-2, wherein the complement inhibitor is a specific inhibitor of the alternative pathway or lectin pathway (published claims 4-5), [0012]-[0013], [0019]-[0020]. The `880 publication further teaches that Kulik et al. showed that pathogenic natural antibodies recognizing Annexin IV are required to develop intestinal ischemia-reperfusion injury. J. Immunol. 2009; 182:5363-5373. U.S. Patent Application Publication No. 2011/0014270 discloses lipids, annexins, and lipid-annexin complexes for use in the prevention and/or treatment of ischemia-reperfusion injury and reperfusion injury associated with a variety of diseases and conditions [0007].
The `270 publication teaches and claims methods treat ischemia-reperfusion injury or a disease or condition associated with ischemia-reperfusion injury in an individual, comprising administering to the individual a therapeutic agent for the treatment of ischemia-reperfusion injury or a disease or condition associated with ischemia-reperfusion injury, wherein the agent is linked to a targeting agent that selectively binds to annexin-4 expressed on the surface of a cell that is in or adjacent to a tissue that is undergoing, or is at risk of undergoing, ischemia-reperfusion injury, or to a phospholipid expressed on the surface of a cell that is in or adjacent to a tissue that is undergoing, or is at risk of undergoing, ischemia-reperfusion injury, wherein the targeting agent is an antibody or antigen-binding fragment thereof, wherein the antibody is a competitive inhibitor of an antibody that selectively binds to annexin-4 expressed on the surface of a cell or to a phospholipid expressed on the surface of a cell and that catalyzes the initiation and development of ischemia-reperfusion injury [0019]. The `270 teaches the anti-protein monoclonal antibody that catalyzes ischemia-reperfusion injury and specifically recognizes annexin-4 (e.g., referred to herein as MAb B4 or C2) [0026] [0037] [0038] (comprising the claimed sequences). The `270 publication provides deliverable therapeutic agents and methods that prevent or reduce ischemia-reperfusion injury and reperfusion injury in an individual [0006].
The reference teaching differs from the claimed invention only in the recitation of MAp44 fragment.
However, the `880 publication further teaches that an additional related protein, MBL/Ficolin Associated Protein (MAP-1, aka MAp44), which is present in low serum levels compared to MASP-1 and MASP-3, has been reported to function as a local lectin pathway specific complement inhibitor. Skjodt et al., Molecular Immunology, 47:2229-30 (2010). Accordingly MAP-1 (aka MAp44) itself, or fragments of MAP-1, may be useful in the present invention as an inhibitor of MASP, and accordingly, as a lectin-pathway-specific inhibitor of complement activation. [0324].
However, the `107 publication teaches a construct of a fusion protein comprising MAp44 fragment that is at least 50, 60, 70, 80, 90 or 100 amino acids of referenced/claimed SEQ ID NO: 1/144 long conjugated to toxin (see claims 1, 5, 6, and ¶¶91, 178, 52-53). MAp44 polypeptide is capable of binding to mannan-binding lectin, H-ficolin, L-ficolin or M-ficolin. [0102] Methods of treating a subject suffering from a collectin-dependent complement mediated condition associated with an ischemia-reperfusion injury are also embodiments and said methods can be practice by administering an amount of a MAP44 agent effective to inhibit collectin-dependent complement activation. In some embodiments, the ischemia reperfusion injury is associated with aortic aneurysm repair, cardiopulmonary bypass, vascular reanastomosis in connection with organ transplants and/or extremity/digit replantation, stroke, myocardial infarction, and hemodynamic resuscitation following shock and/or Surgical procedures. [0235] The putative protein product encompasses CUB1-EGF-CUB2-CCP1 (363 amino acids) of MASP-1/-3 and additional 17 unique amino acids (KNEIDLESELKSEQVTE (SEQ ID NO 4) C-terminally. The calculated MW of the polypeptide product was 44 kDa, and we have named this candidate protein “mannan-binding lectin-associated protein of 44 kDa, or “MAp44”.
Those of skilled in the art would have a reason to use the MAp44 polypeptide of the `107 (Thiel) publication as a substitute for the complement inhibitor taught by Arkinson et al, `880 (Rohrer) publication because, like the complement inhibitors taught by the `880/Rohrer publication, MAp44 polypeptide inhibits collectin-dependent complement activation. Substituting a known element for another, to yield the known result, is obvious. See KSR, 550 U.S. at 416, 421 (2007).
Claims 59-60 are included because both the prior art and the instant claims are directed to the same antibody, B4. Thus, the claimed functional properties recited in the claims are considered inherent properties.
"[W]hen a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result." KSR Int'l v. Teleflex Inc., 550 U.S. 398,416 (2007).
Further, “The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc. 550 U.S. 398, 416 (2007).
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
14. Claims 57-59 and 67-70 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2008/021290 (Hood) in view of WO2014116880 (Rohrer) or US20110014270A.
The teachings of the `880 (Rohrer) publication, the `270 (Holers) publication have been discussed, supra.
The reference teaching differs from the claimed invention only in the recitation of MAp44 fragment.
The '290 teaches SEMAP44 has 380 aa of SEQ ID NO: 14668 comprising claimed SEQ ID NO: 46 of heart-specific protein (see page 59, lines 10 and 22, Tables 43A, 53A, 78A).
It would have been obvious before the effective filing date of the claimed invention to target the B4 antibody to the heart using the heart-specific protein MAp44 taught by the 290 in the treatment of ischemia-reperfusion injury or a disease or condition associated with ischemia-reperfusion injury to guide and ensure the delivery of the anti-Annexin antibody, B4, to site of action and to limit toxicity/side effects of the B4 antibody.
The referenced SEMAP44 fragment of 380 amino acids comprises the claimed fragments of 1-37, 1-176, 1-296, 1-363 of SEQ ID NO: 44 and it comprises also SEQ ID NOs: 46, 48, 50 and 52.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
15. No claim is allowed.
16. The art made of record and not relied upon is considered pertinent to applicant's disclosure:
(i) Qiao et al. Role of pathogenic natural antibodies and complement in a murine model of spinal cord injury (P4051). J Immunol May 1, 2013, 190 (1 Supplement) 131.26.
Qiao et al teaches the use of a single chain antibody (scFv) derived from the anti-annexin A4 hybridoma as a targeting vehicle for delivery of a complement inhibitor after SCI (by linking the scFv to the complement inhibitor, Crry). The scFv-Crry construct, and to a lesser degree scFv alone, were protective against SCI, as measured by improved functional recovery, tissue sparing and demyelination. Data indicate an important role for self-reactive IgM in initiating complement activation after SCI, and that post-SCI neoepitopes represent therapeutic targets.
(ii) Holt et al. Association between endogenous complement inhibitor and myocardial salvage in patients with myocardial infarction. European heart journal. Acute cardiovascular care, (2014 Mar) Volume 3, Number 1, pp. 3-9. Electronic Publication Date:30 Sep 2013.
Holt et al teaches Plasma levels of MAp44, MASP-1, and MASP-3 are significantly higher in patients with MI compared to healthy control persons, but are not associated with short-term outcome measured as salvage index and final infarct.
17. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAHER M HADDAD whose telephone number is (571)272-0845. The examiner can normally be reached on Monday-Friday from7:00AM to 4:30PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu, can be reached at telephone number 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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December 7, 2025
/MAHER M HADDAD/ Primary Examiner, Art Unit 1644