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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 03/23/2026 has been entered.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 1, 20, 21, 24, 76, 77, and 79-87 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains 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.
The nature of the invention relates to anti-C1q antibodies and their use in treating or preventing blood disorders associated with C1q mediated activation of the classical complement pathway.
The claims are drawn to a method of treating, reducing the risk of developing, or preventing a blood disorder associated with C1q mediated activation of the classical complement pathway, in particular the broad categories of thrombosis, drug-induced hematologic disorders, and infections.
The specification teaches that the full-length anti-C1q antibody Mab1 (VH/VL of SEQ ID NOs: 33 and 37) inhibits complement-mediated hemolysis in blood samples obtained from patients having cold agglutinin disease (CAD), in which red blood cells (RBCs) become coated with the major immune cell ligands (or opsonins) of the complement cascade including C1q, C3b, C4b, and C5b which drive RBC clearance via extravascular or intravascular hemolysis. The anti-C1q antibody Mab1 effectively arrests both intravascular and extravascular RBC lysis in CAD serum samples by inhibiting complement deposition (Example 1). Similarly, the anti-C1q antibody Mab2 (VH/VL of SEQ ID NOs: 4 and 8) and FabA (VH/VL of SEQ ID NOs: 39 and 40) inhibit hemolysis and complement deposit in blood samples from CAD patients (Example 2). Further, the anti-C1q antibody Mab1 also completely inhibited complement deposition in blood samples from warm autoimmune hemolytic anemia (wAIHA) patients (Example 5). Additionally, the anti-C1q Mab inhibited classical complement activation by PF4/heparin complexes (Example 3).
While the specification exemplifies specific disorders associated with C1q-mediated classical complement activation such as CAD, wAIHA, and HIT/HITT, it does not provide sufficient evidence to establish C1q-mediated classical pathway activation as a therapeutic target across every disorder within the broad categories recited, including thromboses, drug-induced hematological disorders, and infections. Indeed, the prior art does not appear to establish as a general rule that classical pathway activation predictably occurs in most, if not all, types of thrombotic and drug-induced hematological disorders. Without further guidance provided in the specification, artisans would necessarily have to engage in undue trial and error experimentation to identify members of these broad categories that are associated with C1q mediated classical pathway activation and for which C1q inhibition would reasonably be expected to provide therapeutic benefit.
With respect to infections, the mere occurrence of classical complement activation does not readily establish that that C1q activation contributes to disease pathogenesis nor that C1q inhibition would be therapeutically beneficial. Indeed, the prior art teaches that, during infections, activation of C1q and the classical complement pathway constitutes a normal component of innate immune defense against pathogens (Dunkelberger et al, see Abstract, Complement Origins and Actions, Regulation of Complement Activation, and Effectors of the Complement Systems sections, of record), and C1q deficiency aggravates and/or increases susceptibility to bacterial and viral infections (Schulz et al, see Abstract, Introduction, and Sections 5.1 and 5.3, of record). Thus, the association of C1q mediated classical pathway activation with disease or disorder does not predictably establish a pathological role for C1q activation in infections.
A person of ordinary skill in the art at the time of filing would have had a background in complement system biology and experience in diagnosing and treating hematologic disorders. Even at this high level of skill, however, determining whether a given disorder encompassed by the broad categories recited –e.g. thrombosis, drug-induced hematologic disorders, infections, —would receive therapeutic benefit from inhibiting C1q mediated complement activation requires additional, unpredictable research. Thus, without further guidance, artisans would have to engage in undue trial-and-error experimentation to determine which blood disorders encompassed by the can would receive therapeutic benefit from inhibiting C1q mediated complement activation. Claims 20, 21, 24, 76, 77, and 79-87 incorporate limitations of claim 1 but do not cure the deficiencies of claim 1 and are thus also rejected.
Therefore, the specification is not enabling over the full scope of the claims.
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, 20, 21, 76, 77, and 79-87 are rejected under 35 U.S.C. 103 as being unpatentable over Rosenthal et al (WO2016073685A1, of record), hereinafter Rosenthal, in view of Khandelwal et al (Khandelwal, Sanjay, et al. "Polyreactive IgM initiates complement activation by PF4/heparin complexes through the classical pathway." Blood, The Journal of the American Society of Hematology 132.23 (2018): 2431-2440), hereinafter Khandelwal, and Arepally et al (Arepally, Gowthami M. "Heparin-induced thrombocytopenia." Blood, The Journal of the American Society of Hematology 129.21 (2017): 2864-2872), hereinafter Arepally.
Rosenthal discloses a method of treating or preventing a disease associated with complement activation in a subject comprising administering an anti-C1q antibody to the subject (Abstract, Brief Summary: Para. 0021-0023, in particular, and Para. 0229). Prevention includes providing prophylaxis with respect to occurrence or recurrence of a particular disease, disorder, or condition in an individual, including at risk individuals (Para. 0040) whereas an individual is successfully "treated", for example, if one or more symptoms associated with a particular disease, disorder, or condition are mitigated or eliminated (Para. 0042). The anti-C1q antibody is, for example, the murine M1 clone having the VH and VL chains of SEQ ID NOs: 22 and 21, respectively (corresponding to SEQ ID NOs: 4 and 8 of the instant claims and fully comprising the CDRs of SEQ ID NOs: 5, 6, 7, 9, 10, and 11 of the instant claims) (Example 1: Para. 0252-0253). Alternatively, the anti-C1q antibody can be selected from one of the humanized clones having the VH chains of SEQ ID NOs: 1-4 (corresponding to SEQ ID NOs: 31-34 of the instant claims) and the VL chains of SEQ ID NOs: 5-8 (corresponding to SEQ ID NOs: 35-38 of the instant claims) ( Example 1: Para. 0259-0262 and Para. 0268-0271). The antibody can be an antibody fragment such as a Fab fragment (Para. 0058, Para. 0149-0150, and “Antibody Fragments” section: Para. 0169-0170). The anti-C1q antibody can be administered by infusion or intravenous, intramuscular, or subcutaneous routes (Para. 0220). The minimal structure required for the anti-C1q Fab to possess the functional properties set forth in the claims—selective C1q inhibition within the subject’s blood space, shorter half-life relative to a full-length antibody, and rapid clearance—are the heavy and light chain CDRs recited in instant claim 1. As such, the anti-C1q Fab of Rosenthal having the same structure possess the functional properties recited in the instant claims. Further, infusion/intravenous administration, e.g., necessarily introduces the anti-C1q antibody or Fab fragment into the circulation for distribution through the blood (a mixture of red blood cells, white blood cells, and platelets) and vascular system (veins, venules, capillaries, arterioles, and arteries), including highly vascularized tissues (e.g. alveoli and glomeruli).
Rosenthal does not teach that the disorder associated with complement activation is heparin-induced thrombocytopenia (HIT)/heparin-induced thrombocytopenia and thrombosis (HITT). Of note, HIT/HITT are both considered antibody-mediated thrombocytopenias or drug-induced hematological disorders.
However, Khandelwal teaches that IgM facilitates complement and antigen deposition on B cells in vitro and in patients receiving heparin, and anti-C1q antibody prevents IgM-mediated complement activation by PF4/heparin complexes, indicating classical pathway involvement. Thus, polyreactive IgM binds PF4/heparin, triggers activation of the classical complement pathway, and promotes antigen and complement deposition on B cells, leading to the development of antigen-specific antibodies that mediate heparin-induced thrombocytopenia (HIT) (Abstract and Discussion).
Arepally further teaches that, following formation of antibodies to PF4/heparin complexes, a subset of seropositive patients develops thrombocytopenia and can progress to life-threatening thrombotic complications, i.e. HIT with thrombosis (HITT). In particular, the binding of HIT antibodies to platelet FcγRIIA induces platelet activation and is accompanied by robust thrombin generation, thereby contributing to the thrombotic complications of HIT.
It would have been obvious to one of ordinary skill in the art to administer the anti-C1q antibody of Rosenthal to a subject having HIT or HITT. One of ordinary skill in the art would have been motivated to do so because anti-C1q antibodies administered, e.g., by infusion or intravenously, can be used to treat or prevent complement-mediated disorders as taught by Rosenthal; and polyreactive IgM antibodies initiate classical complement activation in response to PF4/heparin complexes, which can contribute to the development of HIT as taught by Khandelwal. In a subset of patients, HIT can be accompanied by thrombotic complications, termed HITT, as taught by Arepally. Because PF4/heparin complexes are implicated in the pathogenesis of HIT/HITT, one of ordinary skill in the art would have reasonably expected for administration of an anti-C1q antibody to inhibit the complement-mediated processes associated with HIT and thereby reduce the occurrence of at least some of its pathological consequences, including thrombosis, as they occur in HITT. Of note, the wherein clauses of the instant claims that recite that C1q selective inhibition “spares C1q activity outside the subject’s blood space” and “reduces tissue damage in highly vascularized tissues” are intended results of the claimed method that do not carry patentable weight. As such, the anti-C1q antibody and method of treatment disclosed by the combined teachings of the prior art are not patentably distinct from the instantly claimed method.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Rosenthal in view of Khandelwal and Arepally, as applied to claims 1, 20, 21, 76, 77, and 79-87 above, and further in view of Yednock et al (US20170152309A1, of record), hereinafter Yednock.
The teachings of Rosenthal in view of Khandelwal and Arepally have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-C1q Fab fragment comprises heavy and light chains of SEQ ID NOs: 39 and 40, respectively.
However, Yednock discloses a method of treating or preventing a disease associated with complement activation in a subject comprising administering an anti-C1q antibody Fab fragment to the subject, wherein the anti-C1q Fab fragment has the heavy and lights chains set forth in SEQ ID NOs: 1 and 2, respectively (corresponding to SEQ ID NOs: 39 and 40 of the instant claims). It would have been obvious to modify the method of treating or preventing a complement associated disorder subject disclosed by Rosenthal such that the anti-C1q Fab fragment is substituted with that of Yednock having the heavy and light chains of SEQ ID NOs: 1 and 2. One of ordinary skill in the art would have been motivated to do so since the anti-C1q Fab fragments of Rosenthal and Yednock 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). Therefore one of ordinary skill in the art would reasonably expect for administration of the anti-C1q Fab fragment disclosed by Yednock to inhibit the complement-mediated processes associated with HIT and thereby reduce the occurrence of at least some of its pathological consequences, including thrombosis that occurs in HITT.
Claims 1, 20, 21, 76, 77, and 79-87 are rejected under 35 U.S.C. 103 as being unpatentable over Rosenthal et al (WO2016073685A1), hereinafter Rosenthal, in view of Peerschke et al (Peerschke, Ellinor I B et al. “Classical complement pathway activation in immune thrombocytopenia purpura: inhibition by a novel C1s inhibitor.” British journal of haematology vol. 173,6 (2016): 942-5. doi:10.1111/bjh.13648), hereinafter Peerschke.
Rosenthal discloses a method of treating or preventing a disease associated with complement activation in a subject comprising administering an anti-C1q antibody to the subject (Abstract, Brief Summary: Para. 0021-0023, in particular, and Para. 0229). Prevention includes providing prophylaxis with respect to occurrence or recurrence of a particular disease, disorder, or condition in an individual, including at risk individuals (Para. 0040) whereas an individual is successfully "treated", for example, if one or more symptoms associated with a particular disease, disorder, or condition are mitigated or eliminated (Para. 0042). The anti-C1q antibody is, for example, the murine M1 clone having the VH and VL chains of SEQ ID NOs: 22 and 21, respectively (corresponding to SEQ ID NOs: 4 and 8 of the instant claims and fully comprising the CDRs of SEQ ID NOs: 5, 6, 7, 9, 10, and 11 of the instant claims) (Example 1: Para. 0252-0253). Alternatively, the anti-C1q antibody can be selected from one of the humanized clones having the VH chains of SEQ ID NOs: 1-4 (corresponding to SEQ ID NOs: 31-34 of the instant claims) and the VL chains of SEQ ID NOs: 5-8 (corresponding to SEQ ID NOs: 35-38 of the instant claims) ( Example 1: Para. 0259-0262 and Para. 0268-0271). The antibody can be an antibody fragment such as a Fab fragment (Para. 0058, Para. 0149-0150, and “Antibody Fragments” section: Para. 0169-0170). The anti-C1q antibody can be administered by infusion or intravenous, intramuscular, or subcutaneous routes (Para. 0220). The minimal structure required for the anti-C1q Fab to possess the functional properties set forth in the claims—selective C1q inhibition within the subject’s blood space, shorter half-life relative to a full-length antibody, and rapid clearance—are the heavy and light chain CDRs recited in instant claim 1. As such, the anti-C1q Fab of Rosenthal having the same structure possess the functional properties recited in the instant claims. Further, infusion/intravenous administration, e.g., necessarily introduces the anti-C1q antibody or Fab fragment into the circulation for distribution through the blood (a mixture of red blood cells, white blood cells, and platelets) and vascular system (veins, venules, capillaries, arterioles, arteries), including in highly vascularized tissues (e.g. alveoli and glomeruli).
Rosenthal does not teach that the complement-associated disease is immune thrombocytopenia (ITP) (an autoimmune thrombocytopenia).
However, Peerschke teaches that ITP is characterized by immune mediated platelet destruction and decreased platelet production; and that complement activation plays a role in the pathogenesis of ITP (para. 1 on page 1). Inhibition of the classical pathway, in particular, blocks complement deposition on platelets in ITP, including downstream C3b and C5b-9 deposition (see paragraph 2 on page 1 and paragraph 5 on page 2).
It would have been obvious to one of ordinary sill in the art to administer the anti-C1q antibody of Rosenthal to a subject having immune thrombocytopenia (ITP). One of ordinary skill in the art would have been motivated to do so because anti-C1q antibodies administered, e.g., by infusion or intravenously, can be used to treat or prevent complement-mediated disorders as taught by Rosenthal; and complement activation plays a role in ITP pathogenesis, with blockade of the classical pathway, in particular, reducing complement deposition on platelets, including downstream C3b and C5b-9 deposition as taught by Peerschke. Because classical complement activation can contribute to platelet destruction in ITP, one of ordinary skill in the art would reasonably expect for administration of the anti-C1q antibody of Rosenthal to inhibit classical complement activation associated with ITP and thereby reduce the occurrence of at least some of the pathological symptoms of ITP, including platelet destruction. Of note, the wherein clauses of the instant claims that recite that C1q selective inhibition “spares C1q activity outside the subject’s blood space” and “reduces tissue damage in highly vascularized tissues” are intended results of the claimed method that do not carry patentable weight. As such, the anti-C1q antibody and method of treatment disclosed by the combined teachings of the prior art are not patentably distinct from the instantly claimed method.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Rosenthal in view of Peerschke, as applied to claims 1, 20, 21, 76, 77, and 79-87 above, and further in view of Yednock et al (US20170152309A1, of record), hereinafter Yednock.
The teachings of Rosenthal in view of Peerschke have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-C1q Fab fragment comprises heavy and light chains of SEQ ID NOs: 39 and 40, respectively.
However, Yednock discloses a method of treating or preventing a disease associated with complement activation in a subject comprising administering an anti-C1q antibody Fab fragment to the subject, wherein the anti-C1q Fab fragment has the heavy and lights chains set forth in SEQ ID NOs: 1 and 2, respectively (corresponding to SEQ ID NOs: 39 and 40 of the instant claims). It would have been obvious to modify the method of treating or preventing a complement associated disorder subject disclosed by the issued claims such that the anti-C1q Fab fragment is substituted with that of Yednock having the heavy and light chains of SEQ ID NOs: 1 and 2. One of ordinary skill in the art would have been motivated to do so since the anti-C1q Fab fragments of the issued claims and Yednock 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). Therefore one of ordinary skill in the art would reasonably expect for administration of the anti-C1q Fab fragment disclosed by Yednock to inhibit classical complement activation associated with ITP and thereby reduce the occurrence of at least some of the pathological symptoms of ITP, including platelet destruction.
Claims 1, 20, 21, 76, 77, and 79-87 are rejected under 35 U.S.C. 103 as being unpatentable over Rosenthal et al (WO2016073685A1), hereinafter Rosenthal, in view of Hurd et al (Hurd, E R et al. “Increased C1q binding immune complexes in Felty's syndrome: comparison with uncomplicated rheumatoid arthritis.” Arthritis and rheumatism vol. 22,7 (1979): 697-702. doi:10.1002/art.1780220702), hereinafter Hurd.
Rosenthal discloses a method of treating or preventing a disease associated with complement activation in a subject comprising administering an anti-C1q antibody to the subject (Abstract, Brief Summary: Para. 0021-0023, in particular, and Para. 0229). Prevention includes providing prophylaxis with respect to occurrence or recurrence of a particular disease, disorder, or condition in an individual, including at risk individuals (Para. 0040) whereas an individual is successfully "treated", for example, if one or more symptoms associated with a particular disease, disorder, or condition are mitigated or eliminated (Para. 0042). The anti-C1q antibody is, for example, the murine M1 clone having the VH and VL chains of SEQ ID NOs: 22 and 21, respectively (corresponding to SEQ ID NOs: 4 and 8 of the instant claims and fully comprising the CDRs of SEQ ID NOs: 5, 6, 7, 9, 10, and 11 of the instant claims) (Example 1: Para. 0252-0253). Alternatively, the anti-C1q antibody can be selected from one of the humanized clones having the VH chains of SEQ ID NOs: 1-4 (corresponding to SEQ ID NOs: 31-34 of the instant claims) and the VL chains of SEQ ID NOs: 5-8 (corresponding to SEQ ID NOs: 35-38 of the instant claims) ( Example 1: Para. 0259-0262 and Para. 0268-0271). The antibody can be an antibody fragment such as a Fab fragment (Para. 0058, Para. 0149-0150, and “Antibody Fragments” section: Para. 0169-0170). The anti-C1q antibody can be administered by infusion or intravenous, intramuscular, or subcutaneous routes (Para. 0220). The minimal structure required for the anti-C1q Fab to possess the functional properties set forth in the claims—selective C1q inhibition within the subject’s blood space, shorter half-life relative to a full-length antibody, and rapid clearance—are the heavy and light chain CDRs recited in instant claim 1. As such, the anti-C1q Fab of Rosenthal having the same structure possess the functional properties recited in the instant claims. Further, infusion/intravenous administration, e.g., necessarily introduces the anti-C1q antibody or Fab fragment into the circulation for distribution through the blood (a mixture of red blood cells, white blood cells, and platelets) and vascular system (veins, venules, capillaries, arterioles, and arteries), including highly vascularized tissues (e.g. alveoli and glomeruli).
Rosenthal does not teach that the complement-associated disease is Felty’s syndrome.
However, Hurd teaches that patients with Felty’s syndrome (FS) had higher levels of C1q binding to immune complexes (IC) in their sera compared to patients without FS, and suggests that complement-fixing IC can play a role in the pathogenesis of neutropenia of FS (abstract).
It would have been obvious to one of ordinary sill in the art to administer the anti-C1q antibody of Rosenthal to a subject having Felty’s syndrome. One of ordinary skill in the art would have been motivated to do so because anti-C1q antibodies administered, e.g., by infusion or intravenously, can be used to treat or prevent complement-mediated disorders as taught by Rosenthal; and patients with Felty’s syndrome have increased levels of C1q binding immune complexes, which can contribute to the neutropenia that occurs in FS. Therefore, one of ordinary skill in the art would reasonably expect for administration of the anti-C1q antibody of Rosenthal to inhibit complement activation associated with Felty’s syndrome and thereby reduce the occurrence of at least some of the pathological symptoms of the disease, including neutropenia. Of note, the wherein clauses of the instant claims that recite that C1q selective inhibition “spares C1q activity outside the subject’s blood space” and “reduces tissue damage in highly vascularized tissues” are intended results of the claimed method that do not carry patentable weight. As such, the anti-C1q antibody and method of treatment disclosed by the combined teachings of the prior art are not patentably distinct from the instantly claimed method.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Rosenthal in view of Peerschke, as applied to claims 1, 20, 21, 76, 77, and 79-87 above, and further in view of Yednock et al (US20170152309A1, of record), hereinafter Yednock.
The teachings of Rosenthal in view of Peerschke have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-C1q Fab fragment comprises heavy and light chains of SEQ ID NOs: 39 and 40, respectively.
However, Yednock discloses a method of treating or preventing a disease associated with complement activation in a subject comprising administering an anti-C1q antibody Fab fragment to the subject, wherein the anti-C1q Fab fragment has the heavy and lights chains set forth in SEQ ID NOs: 1 and 2, respectively (corresponding to SEQ ID NOs: 39 and 40 of the instant claims). It would have been obvious to modify the method of treating or preventing a complement associated disorder subject disclosed by the issued claims such that the anti-C1q Fab fragment is substituted with that of Yednock having the heavy and light chains of SEQ ID NOs: 1 and 2. One of ordinary skill in the art would have been motivated to do so since the anti-C1q Fab fragments of the issued claims and Yednock 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). Therefore one of ordinary skill in the art would reasonably expect for administration of the anti-C1q Fab fragment disclosed by Yednock to inhibit complement activation associated with Felty’s syndrome and thereby reduce the occurrence of at least some of the pathological symptoms of the disease, including neutropenia.
Claims 1, 20, 21, 76, 77, and 79-87 are rejected under 35 U.S.C. 103 as being unpatentable over Rosenthal et al (WO2016073685A1), hereinafter Rosenthal, in view of Jaime-Perez et al (Jaime-Pérez, José Carlos et al. “Evans syndrome: clinical perspectives, biological insights and treatment modalities.” Journal of blood medicine vol. 9 171-184. 10 Oct. 2018, doi:10.2147/JBM.S176144), hereinafter Jaime-Perez and Peerschke et al (Peerschke, Ellinor I B et al. “Classical complement pathway activation in immune thrombocytopenia purpura: inhibition by a novel C1s inhibitor.” British journal of haematology vol. 173,6 (2016): 942-5. doi:10.1111/bjh.13648), hereinafter Peerschke.
Rosenthal discloses a method of treating or preventing a disease associated with complement activation – such as autoimmune hemolytic anemias— in a subject comprising administering an anti-C1q antibody to the subject (Abstract, Brief Summary: Para. 0021-0023, in particular, and Para. 0229). Prevention includes providing prophylaxis with respect to occurrence or recurrence of a particular disease, disorder, or condition in an individual, including at risk individuals (Para. 0040) whereas an individual is successfully "treated", for example, if one or more symptoms associated with a particular disease, disorder, or condition are mitigated or eliminated (Para. 0042). The anti-C1q antibody is, for example, the murine M1 clone having the VH and VL chains of SEQ ID NOs: 22 and 21, respectively (corresponding to SEQ ID NOs: 4 and 8 of the instant claims and fully comprising the CDRs of SEQ ID NOs: 5, 6, 7, 9, 10, and 11 of the instant claims) (Example 1: Para. 0252-0253). Alternatively, the anti-C1q antibody can be selected from one of the humanized clones having the VH chains of SEQ ID NOs: 1-4 (corresponding to SEQ ID NOs: 31-34 of the instant claims) and the VL chains of SEQ ID NOs: 5-8 (corresponding to SEQ ID NOs: 35-38 of the instant claims) ( Example 1: Para. 0259-0262 and Para. 0268-0271). The antibody can be an antibody fragment such as a Fab fragment (Para. 0058, Para. 0149-0150, and “Antibody Fragments” section: Para. 0169-0170). The anti-C1q antibody can be administered by infusion or intravenous, intramuscular, or subcutaneous routes (Para. 0220). The minimal structure required for the anti-C1q Fab to possess the functional properties set forth in the claims—selective C1q inhibition within the subject’s blood space, shorter half-life relative to a full-length antibody, and rapid clearance—are the heavy and light chain CDRs recited in instant claim 1. As such, the anti-C1q Fab of Rosenthal having the same structure possess the functional properties recited in the instant claims. Further, infusion/intravenous administration, e.g., necessarily introduces the anti-C1q antibody or Fab fragment into the circulation for distribution through the blood (a mixture of red blood cells, white blood cells, and platelets) and vascular system (veins, venules, capillaries, arterioles, and arteries), including highly vascularized tissues (e.g. alveoli and glomeruli).
Rosenthal does not teach that the complement-associated disease is Evan’s syndrome.
However, Jaime-Perez teaches that Evans syndrome (ES) is a rare and chronic autoimmune disease characterized by autoimmune hemolytic anemia and immune thrombocytopenic purpura (ITP) (abstract).
Peerschke further teaches that complement activation plays a role in the pathogenesis of ITP; and inhibition of the classical pathway, in particular, blocks complement deposition on platelets in ITP, including downstream C3b and C5b-9 deposition (see paragraph 2 on page 1 and paragraph 5 on page 2).
It would have been obvious to one of ordinary skill in the art to administer the anti-C1q antibody of Rosenthal to a subject having Evans syndrome. One of ordinary skill in the art would have been motivated to do so since Evans syndrome is characterized by autoimmune hemolytic anemia (AIHA) and ITP as taught by Jaime-Perez, and AIHA is one of the complement disorders identified by Rosenthal that would receive therapeutic benefit from anti-C1q therapy when administered, e.g. intravenously or by infusion. Further, inhibition of the classical pathway can block complement deposition in ITP and thus mitigate platelet destruction as taught by Peerschke. Therefore, one of ordinary skill in the art would reasonably expect that the anti-C1q antibody of Rosenthal can be used to mitigate AIHA and ITP symptoms and thus treat Evans syndrome in a patient. Of note, the wherein clauses of the instant claims that recite that C1q selective inhibition “spares C1q activity outside the subject’s blood space” and “reduces tissue damage in highly vascularized tissues” are intended results of the claimed method that do not carry patentable weight. As such, the anti-C1q antibody and method of treatment disclosed by the combined teachings of the prior art are not patentably distinct from the instantly claimed method.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Rosenthal in view of Peerschke, as applied to claims 1, 20, 21, 76, 77, and 79-87 above, and further in view of Yednock et al (US20170152309A1, of record), hereinafter Yednock.
The teachings of Rosenthal in view of Peerschke have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-C1q Fab fragment comprises heavy and light chains of SEQ ID NOs: 39 and 40, respectively.
However, Yednock discloses a method of treating or preventing a disease associated with complement activation in a subject comprising administering an anti-C1q antibody Fab fragment to the subject, wherein the anti-C1q Fab fragment has the heavy and lights chains set forth in SEQ ID NOs: 1 and 2, respectively (corresponding to SEQ ID NOs: 39 and 40 of the instant claims). It would have been obvious to modify the method of treating or preventing a complement associated disorder subject disclosed by Rosenthal such that the anti-C1q Fab fragment is substituted with that of Yednock having the heavy and light chains of SEQ ID NOs: 1 and 2. One of ordinary skill in the art would have been motivated to do so since the anti-C1q Fab fragments of Rosenthal and Yednock 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). Therefore one of ordinary skill in the art would reasonably expect for administration of the anti-C1q Fab fragment disclosed by Yednock to can be used to mitigate AIHA and ITP symptoms and thus treat Evans syndrome in a patient.
Claims 1, 20, 21, 76, 77, and 79-87 are rejected under 35 U.S.C. 103 as being unpatentable over Rosenthal et al (WO2016073685A1), hereinafter Rosenthal, in view of Hadley et al (Hadley, Andrew G., and Craig Turner. "Pathophysiology of the alloimmune cytopenias." Alloimmune disorders of pregnancy. Cambridge University Press, Cambridge (UK), 2002. 1-20), hereinafter Hadley.
Rosenthal discloses a method of treating or preventing a disease associated with complement activation in a subject comprising administering an anti-C1q antibody to the subject (Abstract, Brief Summary: Para. 0021-0023, in particular, and Para. 0229). Prevention includes providing prophylaxis with respect to occurrence or recurrence of a particular disease, disorder, or condition in an individual, including at risk individuals (Para. 0040) whereas an individual is successfully "treated", for example, if one or more symptoms associated with a particular disease, disorder, or condition are mitigated or eliminated (Para. 0042). The anti-C1q antibody is, for example, the murine M1 clone having the VH and VL chains of SEQ ID NOs: 22 and 21, respectively (corresponding to SEQ ID NOs: 4 and 8 of the instant claims and fully comprising the CDRs of SEQ ID NOs: 5, 6, 7, 9, 10, and 11 of the instant claims) (Example 1: Para. 0252-0253). Alternatively, the anti-C1q antibody can be selected from one of the humanized clones having the VH chains of SEQ ID NOs: 1-4 (corresponding to SEQ ID NOs: 31-34 of the instant claims) and the VL chains of SEQ ID NOs: 5-8 (corresponding to SEQ ID NOs: 35-38 of the instant claims) ( Example 1: Para. 0259-0262 and Para. 0268-0271). The antibody can be an antibody fragment such as a Fab fragment (Para. 0058, Para. 0149-0150, and “Antibody Fragments” section: Para. 0169-0170). The anti-C1q antibody can be administered by infusion or intravenous, intramuscular, or subcutaneous routes (Para. 0220). The minimal structure required for the anti-C1q Fab to possess the functional properties set forth in the claims—selective C1q inhibition within the subject’s blood space, shorter half-life relative to a full-length antibody, and rapid clearance—are the heavy and light chain CDRs recited in instant claim 1. As such, the anti-C1q Fab of Rosenthal having the same structure possess the functional properties recited in the instant claims. Further, infusion/intravenous administration, e.g., necessarily introduces the anti-C1q antibody or Fab fragment into the circulation for distribution through the blood (a mixture of red blood cells, white blood cells, and platelets) and vascular system (veins, venules, capillaries, arterioles, and arteries), including highly vascularized tissues (e.g. alveoli and glomeruli).
Rosenthal does not teach that the complement-associated disease is neonatal alloimmune thrombocytopenia.
However, Hadley teaches alloimmune thrombocytopenia is caused by maternal immunization to fetal blood cells. In particular, at high concentrations of maternal antibodies to the human platelet antigen-1a (HPA-1a) bind C1q and activate the classical complement cascade, resulting in platelet destruction through lysis or through deposition of C3 fragments, which can enhance recognition and clearance of antibody-sensitized platelets by splenic macrophages (section 1.3.3.1 on Page 13).
It would have been obvious to one of ordinary sill in the art to administer the anti-C1q antibody of Rosenthal to a subject having neonatal alloimmune thrombocytopenia. One of ordinary skill in the art would have been motivated to do so because anti-C1q antibodies administered, e.g., by infusion or intravenously, can be used to treat or prevent complement-mediated disorders as taught by Rosenthal; and maternal anti-HPA antibodies bind C1q and activate the classical complement cascade, resulting in platelet destruction and contributing to the pathogenesis of neonatal alloimmune thrombocytopenia as taught by Hadley. Because anti-HPA antibodies engage C1q and classical complement activation leading to platelet destruction in neonatal alloimmune thrombocytopenia, one of ordinary skill in the art would reasonably expect for administration of the anti-C1q antibody of Rosenthal to inhibit classical complement activation associated with neonatal alloimmune thrombocytopenia and thereby reduce the occurrence of at least some of the pathological symptoms of the disease, including platelet destruction. Of note, the wherein clauses of the instant claims that recite that C1q selective inhibition “spares C1q activity outside the subject’s blood space” and “reduces tissue damage in highly vascularized tissues” are intended results of the claimed method that do not carry patentable weight. As such, the anti-C1q antibody and method of treatment disclosed by the combined teachings of the prior art are not patentably distinct from the instantly claimed method.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Rosenthal in view of Hadley, as applied to claims 1, 20, 21, 76, 77, and 79-87 above, and further in view of Yednock et al (US20170152309A1, of record), hereinafter Yednock.
The teachings of Rosenthal in view of Hadley have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-C1q Fab fragment comprises heavy and light chains of SEQ ID NOs: 39 and 40, respectively.
However, Yednock discloses a method of treating or preventing a disease associated with complement activation in a subject comprising administering an anti-C1q antibody Fab fragment to the subject, wherein the anti-C1q Fab fragment has the heavy and lights chains set forth in SEQ ID NOs: 1 and 2, respectively (corresponding to SEQ ID NOs: 39 and 40 of the instant claims). It would have been obvious to modify the method of treating or preventing a complement associated disorder subject disclosed by Rosenthal such that the anti-C1q Fab fragment is substituted with that of Yednock having the heavy and light chains of SEQ ID NOs: 1 and 2. One of ordinary skill in the art would have been motivated to do so since the anti-C1q Fab fragments of Rosenthal and Yednock 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). Therefore one of ordinary skill in the art would reasonably expect for administration of the anti-C1q Fab fragment disclosed by Yednock to inhibit classical complement activation associated with neonatal alloimmune thrombocytopenia and thereby reduce the occurrence of at least some of the pathological symptoms of the disease, including platelet destruction.
Claims 1, 20, 21, 76, 77, and 79-87 are rejected under 35 U.S.C. 103 as being unpatentable over Rosenthal et al (WO2016073685A1), hereinafter Rosenthal, in view of Sontheimer et al (Sontheimer, Richard D., Emil Racila, and Doina M. Racila. "C1q: its functions within the innate and adaptive immune responses and its role in lupus autoimmunity." Journal of investigative dermatology 125.1 (2005): 14-23), hereinafter Sontheimer.
Rosenthal discloses a method of treating or preventing a disease associated with complement activation in a subject comprising administering an anti-C1q antibody to the subject (Abstract, Brief Summary: Para. 0021-0023, in particular, and Para. 0229). Prevention includes providing prophylaxis with respect to occurrence or recurrence of a particular disease, disorder, or condition in an individual, including at risk individuals (Para. 0040) whereas an individual is successfully "treated", for example, if one or more symptoms associated with a particular disease, disorder, or condition are mitigated or eliminated (Para. 0042). The anti-C1q antibody is, for example, the murine M1 clone having the VH and VL chains of SEQ ID NOs: 22 and 21, respectively (corresponding to SEQ ID NOs: 4 and 8 of the instant claims and fully comprising the CDRs of SEQ ID NOs: 5, 6, 7, 9, 10, and 11 of the instant claims) (Example 1: Para. 0252-0253). Alternatively, the anti-C1q antibody can be selected from one of the humanized clones having the VH chains of SEQ ID NOs: 1-4 (corresponding to SEQ ID NOs: 31-34 of the instant claims) and the VL chains of SEQ ID NOs: 5-8 (corresponding to SEQ ID NOs: 35-38 of the instant claims) ( Example 1: Para. 0259-0262 and Para. 0268-0271). The antibody can be an antibody fragment such as a Fab fragment (Para. 0058, Para. 0149-0150, and “Antibody Fragments” section: Para. 0169-0170). The anti-C1q antibody can be administered by infusion or intravenous, intramuscular, or subcutaneous routes (Para. 0220). The minimal structure required for the anti-C1q Fab to possess the functional properties set forth in the claims—selective C1q inhibition within the subject’s blood space, shorter half-life relative to a full-length antibody, and rapid clearance—are the heavy and light chain CDRs recited in instant claim 1. As such, the anti-C1q Fab of Rosenthal having the same structure possess the functional properties recited in the instant claims. Further, infusion/intravenous administration, e.g., necessarily introduces the anti-C1q antibody or Fab fragment into the circulation for distribution through the blood (a mixture of red blood cells, white blood cells, and platelets) and vascular system (veins, venules, capillaries, arterioles, and arteries), including highly vascularized tissues (e.g. alveoli and glomeruli).
Rosenthal does not teach that the complement-associated disease is systemic lupus erythematosus (SLE).
However, Sontheimer teaches that SLE is an immune complex disease that is associated with activation of the classical complement pathway as reflected by low serum levels of classical pathway complement components during periods of disease activity. In particular, C1q is activated by the binding of its globular head domain to the Fc region of aggregated IgG and IgM molecules in immune complexes. Thus, C1q facilitates tissue injury in the setting of SLE by triggering the elaboration of pro-inflammatory mediators such as C5a and C3a (see “C1q as a facilitating factor for SLE” on page 19).
It would have been obvious to one of ordinary sill in the art to administer the anti-C1q antibody of Rosenthal to a subject having SLE. One of ordinary skill in the art would have been motivated to do so because anti-C1q antibodies administered, e.g., by infusion or intravenously, can be used to treat or prevent complement-mediated disorders as taught by Rosenthal; and C1q facilitates tissue injury in the setting of SLE by triggering the elaboration of pro-inflammatory mediators such as C5a and C3a as taught by Sontheimer. Because C1q and classical complement activation facilitates tissue injury in SLE, one of ordinary skill in the art would reasonably expect for administration of the anti-C1q antibody of Rosenthal to inhibit classical complement activation associated with SLE and thereby mitigate tissue injury in SLE. Of note, the wherein clauses of the instant claims that recite that C1q selective inhibition “spares C1q activity outside the subject’s blood space” and “reduces tissue damage in highly vascularized tissues” are intended results of the claimed method that do not carry patentable weight. As such, the anti-C1q antibody and method of treatment disclosed by the combined teachings of the prior art are not patentably distinct from the instantly claimed method.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Rosenthal in view of Sontheimer, as applied to claims 1, 20, 21, 76, 77, and 79-87 above, and further in view of Yednock et al (US20170152309A1, of record), hereinafter Yednock.
The teachings of Rosenthal in view of Sontheimer have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-C1q Fab fragment comprises heavy and light chains of SEQ ID NOs: 39 and 40, respectively.
However, Yednock discloses a method of treating or preventing a disease associated with complement activation in a subject comprising administering an anti-C1q antibody Fab fragment to the subject, wherein the anti-C1q Fab fragment has the heavy and lights chains set forth in SEQ ID NOs: 1 and 2, respectively (corresponding to SEQ ID NOs: 39 and 40 of the instant claims). It would have been obvious to modify the method of treating or preventing a complement associated disorder subject disclosed by Rosenthal such that the anti-C1q Fab fragment is substituted with that of Yednock having the heavy and light chains of SEQ ID NOs: 1 and 2. One of ordinary skill in the art would have been motivated to do so since the anti-C1q Fab fragments of Rosenthal and Yednock 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). Therefore one of ordinary skill in the art would reasonably expect for administration of the anti-C1q Fab fragment disclosed by Yednock to inhibit classical complement activation associated with SLE and thereby tissue injury in SLE.
Claims 1, 20, 21, 76, 77, and 79-87 are rejected under 35 U.S.C. 103 as being unpatentable over Rosenthal et al (WO2016073685A1), hereinafter Rosenthal, in view of Reti et al (Réti, M., et al. "Complement activation in thrombotic thrombocytopenic purpura." Journal of Thrombosis and Haemostasis 10.5 (2012): 791-798), hereinafter Reti.
Rosenthal discloses a method of treating or preventing a disease associated with complement activation in a subject comprising administering an anti-C1q antibody to the subject (Abstract, Brief Summary: Para. 0021-0023, in particular, and Para. 0229). Prevention includes providing prophylaxis with respect to occurrence or recurrence of a particular disease, disorder, or condition in an individual, including at risk individuals (Para. 0040) whereas an individual is successfully "treated", for example, if one or more symptoms associated with a particular disease, disorder, or condition are mitigated or eliminated (Para. 0042). The anti-C1q antibody is, for example, the murine M1 clone having the VH and VL chains of SEQ ID NOs: 22 and 21, respectively (corresponding to SEQ ID NOs: 4 and 8 of the instant claims and fully comprising the CDRs of SEQ ID NOs: 5, 6, 7, 9, 10, and 11 of the instant claims) (Example 1: Para. 0252-0253). Alternatively, the anti-C1q antibody can be selected from one of the humanized clones having the VH chains of SEQ ID NOs: 1-4 (corresponding to SEQ ID NOs: 31-34 of the instant claims) and the VL chains of SEQ ID NOs: 5-8 (corresponding to SEQ ID NOs: 35-38 of the instant claims) ( Example 1: Para. 0259-0262 and Para. 0268-0271). The antibody can be an antibody fragment such as a Fab fragment (Para. 0058, Para. 0149-0150, and “Antibody Fragments” section: Para. 0169-0170). The anti-C1q antibody can be administered by infusion or intravenous, intramuscular, or subcutaneous routes (Para. 0220). The minimal structure required for the anti-C1q Fab to possess the functional properties set forth in the claims—selective C1q inhibition within the subject’s blood space, shorter half-life relative to a full-length antibody, and rapid clearance—are the heavy and light chain CDRs recited in instant claim 1. As such, the anti-C1q Fab of Rosenthal having the same structure possess the functional properties recited in the instant claims. Further, infusion/intravenous administration, e.g., necessarily introduces the anti-C1q antibody or Fab fragment into the circulation for distribution through the blood (a mixture of red blood cells, white blood cells, and platelets) and vascular system (veins, venules, capillaries, arterioles, and arteries), including highly vascularized tissues (e.g. alveoli and glomeruli).
Rosenthal does not teach that the complement-associated disease is thrombotic thrombocytopenia purpura (TTP).
However, Reti teaches that increased complement activation occurs in patients with acute TTP, and that the classical/lectin and alternative pathways can initiate the terminal pathway in TTP. In addition, the sustained presence of ADAMTS13 inhibitors in patients in complete remission is linked to higher complement activation product levels C4d, C3bBbP and C3a, indicative of the ongoing activation of the classical and alternative pathways. It is suggested that circulating ADAMTS13 immune complexes may initiate complement activation via classical/lectin pathways in patients with TTP and contribute to the microangiopathic process (1st and 3rd paragraphs under Discussion on Page 796; 1st and 3rd paragraphs on Page 797).
It would have been obvious to one of ordinary sill in the art to administer the anti-C1q antibody of Rosenthal to a subject having TTP. One of ordinary skill in the art would have been motivated to do so because anti-C1q antibodies administered, e.g., by infusion or intravenously, can be used to treat or prevent complement-mediated disorders as taught by Rosenthal; and circulating ADAMTS13 immune complexes may initiate complement activation via classical and other pathways in patients with TTP and contribute to the microangiopathic process as suggested by Reti. Because classical complement activation can play a role in TTP, one of ordinary skill in the art would reasonably expect for administration of the anti-C1q antibody of Rosenthal to inhibit classical complement activation associated with TTP and thereby reduce the occurrence of at least some of the pathological symptoms of the disease, such as microangiopathic processes. Of note, the wherein clauses of the instant claims that recite that C1q selective inhibition “spares C1q activity outside the subject’s blood space” and “reduces tissue damage in highly vascularized tissues” are intended results of the claimed method that do not carry patentable weight. As such, the anti-C1q antibody and method of treatment disclosed by the combined teachings of the prior art are not patentably distinct from the instantly claimed method.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Rosenthal in view of Reti, as applied to claims 1, 20, 21, 76, 77, and 79-87 above, and further in view of Yednock et al (US20170152309A1, of record), hereinafter Yednock.
The teachings of Rosenthal in view of Reti have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-C1q Fab fragment comprises heavy and light chains of SEQ ID NOs: 39 and 40, respectively.
However, Yednock discloses a method of treating or preventing a disease associated with complement activation in a subject comprising administering an anti-C1q antibody Fab fragment to the subject, wherein the anti-C1q Fab fragment has the heavy and lights chains set forth in SEQ ID NOs: 1 and 2, respectively (corresponding to SEQ ID NOs: 39 and 40 of the instant claims). It would have been obvious to modify the method of treating or preventing a complement associated disorder subject disclosed by Rosenthal such that the anti-C1q Fab fragment is substituted with that of Yednock having the heavy and light chains of SEQ ID NOs: 1 and 2. One of ordinary skill in the art would have been motivated to do so since the anti-C1q Fab fragments of Rosenthal and Yednock 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). Therefore one of ordinary skill in the art would reasonably expect for administration of the anti-C1q Fab fragment disclosed by Yednock to inhibit classical complement activation associated with TTP and thereby reduce the occurrence of at least some of the pathological symptoms of the disease.
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, 20, 21, 76, 77, and 79-87 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 10316081B2 in view of Rosenthal (WO2016073685A1, of record), hereinafter Rosenthal in view of Khandelwal et al (Khandelwal, Sanjay, et al. "Polyreactive IgM initiates complement activation by PF4/heparin complexes through the classical pathway." Blood, The Journal of the American Society of Hematology 132.23 (2018): 2431-2440), hereinafter Khandelwal, and Arepally et al Arepally, Gowthami M. "Heparin-induced thrombocytopenia." Blood, The Journal of the American Society of Hematology 129.21 (2017): 2864-2872), hereinafter Arepally.
The issued claims recite a humanized anti-C1 antibody comprising the VH chains of SEQ ID NOs: 1-4 and the VL chains of SEQ ID NOs: 5-8, corresponding to SEQ ID NOs: 31-34 and 35-38, respectively, and fully comprising the CDRs of SEQ ID NOs: 5, 6, 7, 9, 10, and 11 of the instant claims (issued claim 1). The antibody can be an antigen-binding fragment such as a Fab fragment (issued claim 10). The minimal structure required for the anti-C1q Fab to possess the functional properties set forth in the claims—selective C1q inhibition within the subject’s blood space, shorter half-life relative to a full-length antibody, and rapid clearance—are the heavy and light chain CDRs recited in instant claim 1. As such, the anti-C1q Fab of the issued claims having the same structure possess the functional properties recited in the instant claims.
The issued claims do not recite a method of treating, reducing the risk of developing, or preventing a blood disorder recited in the claims, such as heparin-induced thrombocytopenia (HIT)/heparin-induced thrombocytopenia and thrombosis (HITT). Further, the issued claims do not recite routes of administration of the anti-C1q Fab.
However, Rosenthal discloses a method of treating or preventing a disease associated with complement activation – such as autoimmune hemolytic anemias— in a subject comprising administering an anti-C1q antibody to the subject (Abstract, Brief Summary: Para. 0021-0023, in particular, and Para. 0229). Prevention includes providing prophylaxis with respect to occurrence or recurrence of a particular disease, disorder, or condition in an individual, including at risk individuals (Para. 0040) whereas an individual is successfully "treated", for example, if one or more symptoms associated with a particular disease, disorder, or condition are mitigated or eliminated (Para. 0042). The anti-C1q antibody can be administered by infusion or intravenous, intramuscular, or subcutaneous routes (Para. 0220). Infusion/intravenous administration, e.g. necessarily introduces the anti-C1q antibody or Fab fragment into the circulation for distribution through the blood (a mixture of red blood cells, white blood cells, and platelets) and vascular system (veins, venules, capillaries, arterioles, and arteries), including highly vascularized tissues (e.g. alveoli and glomeruli).
Khandelwal further teaches that IgM facilitates complement and antigen deposition on B cells in vitro and in patients receiving heparin, and anti-C1q antibody prevents IgM-mediated complement activation by PF4/heparin complexes, indicating classical pathway involvement. Thus, polyreactive IgM binds PF4/heparin, triggers activation of the classical complement pathway, and promotes antigen and complement deposition on B cells, leading to the development of antigen-specific antibodies that mediate heparin-induced thrombocytopenia (HIT) (Abstract and Discussion).
Arepally further teaches that, following formation of antibodies to PF4/heparin complexes, a subset of seropositive patients develops thrombocytopenia and can progress to life-threatening thrombotic complications, i.e. HIT with thrombosis (HITT). In particular, the binding of HIT antibodies to platelet FcγRIIA induces platelet activation and is accompanied by robust thrombin generation, thereby contributing to the thrombotic complications of HIT.
It would have been obvious to one of ordinary skill in the art to administer the anti-C1q antibody of the issued claims to a subject having HIT or HITT according to the methods of treating a complement associated disorder taught by Rosenthal. One of ordinary skill in the art would have been motivated to do so because anti-C1q antibodies administered, e.g., by infusion or intravenously, can be used to treat or prevent complement-mediated disorders as taught by Rosenthal; and polyreactive IgM antibodies initiate classical complement activation in response to PF4/heparin complexes, which can contribute to the development of HIT as taught by Khandelwal. In a subset of patients, HIT can be accompanied by thrombotic complications, termed HITT, as taught by Arepally. Because PF4/heparin complexes are implicated in the pathogenesis of HIT/HITT, one of ordinary skill in the art would have reasonably expected for administration of the anti-C1q antibody of the issued claims to inhibit the complement-mediated processes associated with HIT and thereby reduce the occurrence of at least some of its pathological symptoms, including thrombosis, as they occur in HITT. Of note, the wherein clauses of the instant claims that recite that C1q selective inhibition “spares C1q activity outside the subject’s blood space” and “reduces tissue damage in highly vascularized tissues” are intended results of the claimed method that do not carry patentable weight. As such, the anti-C1q antibody of the issued claims and method of treatment disclosed by the combined teachings of the prior art are not patentably distinct from the instantly claimed method.
Claim 24 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 10316081B2 in view of Rosenthal, Khandelwal and Arepally, as applied to claims 1, 20, 21, 76, 77, and 79-87 above, and further in view of Yednock et al (US20170152309A1, of record), hereinafter Yednock.
The teachings of the issued claims in view of Rosenthal, Khandelwal and Arepally have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-C1q Fab fragment comprises heavy and light chains of SEQ ID NOs: 39 and 40, respectively.
However, Yednock discloses a method of treating or preventing a disease associated with complement activation in a subject comprising administering an anti-C1q antibody Fab fragment to the subject, wherein the anti-C1q Fab fragment has the heavy and lights chains set forth in SEQ ID NOs: 1 and 2, respectively (corresponding to SEQ ID NOs: 39 and 40 of the instant claims). It would have been obvious to modify the method of treating or preventing a complement associated disorder subject disclosed by the issued claims such that the anti-C1q Fab fragment is substituted with that of Yednock having the heavy and light chains of SEQ ID NOs: 1 and 2. One of ordinary skill in the art would have been motivated to do so since the anti-C1q Fab fragments of the issued claims and Yednock 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). Therefore one of ordinary skill in the art would reasonably expect for administration of the anti-C1q Fab fragment disclosed by Yednock to inhibit the complement-mediated processes associated with HIT and thereby reduce the occurrence of at least some of its pathological symptoms, including thrombosis, as they occur in HITT.
Claims 1, 20, 21, 24, 76, 77, and 79-87 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10723788B2 in view of Rosenthal (WO2016073685A1, of record), hereinafter Rosenthal in view of Khandelwal et al (Khandelwal, Sanjay, et al. "Polyreactive IgM initiates complement activation by PF4/heparin complexes through the classical pathway." Blood, The Journal of the American Society of Hematology 132.23 (2018): 2431-2440), hereinafter Khandelwal, and Arepally et al Arepally, Gowthami M. "Heparin-induced thrombocytopenia." Blood, The Journal of the American Society of Hematology 129.21 (2017): 2864-2872), hereinafter Arepally.
The issued claims recite an antibody Fab fragment that binds to C1q and neutralizes a biological activity of C1q, comprising the VH chains of SEQ ID NOs: 5-8 and the VL chains of SEQ ID NOs: 9-12, corresponding to SEQ ID NOs: 31-34 and 35-38, respectively, and fully comprising the CDRs of SEQ ID NOs: 5, 6, 7, 9, 10, and 11 of the instant claims (issued claims 2-3, 12, and 14), wherein the antibody Fab fragment is humanized (issued claim 5). The anti-C1q Fab can also have a heavy and light chain of SEQ ID NOs: 1 and 2, corresponding to SEQ ID NOs: 39 and 40 of the instant claims (issued claim 1). The minimal structure required for the anti-C1q Fab to possess the functional properties set forth in the claims—selective C1q inhibition within the subject’s blood space, shorter half-life relative to a full-length antibody, and rapid clearance—are the heavy and light chain CDRs recited in instant claim 1. As such, the anti-C1q Fab of the issued claims having the same structure possess the functional properties recited in the instant claims.
The issued claims do not recite a method of treating, reducing the risk of developing, or preventing a blood disorder recited in the claims, such as heparin-induced thrombocytopenia (HIT)/heparin-induced thrombocytopenia and thrombosis (HITT). Further, the issued claims do not recite routes of administration of the anti-C1q Fab.
However, Rosenthal discloses a method of treating or preventing a disease associated with complement activation – such as autoimmune hemolytic anemias— in a subject comprising administering an anti-C1q antibody to the subject (Abstract, Brief Summary: Para. 0021-0023, in particular, and Para. 0229). Prevention includes providing prophylaxis with respect to occurrence or recurrence of a particular disease, disorder, or condition in an individual, including at risk individuals (Para. 0040) whereas an individual is successfully "treated", for example, if one or more symptoms associated with a particular disease, disorder, or condition are mitigated or eliminated (Para. 0042). The anti-C1q antibody can be administered by infusion or intravenous, intramuscular, or subcutaneous routes (Para. 0220). Infusion/intravenous administration, e.g. necessarily introduces the anti-C1q antibody or Fab fragment into the circulation for distribution through the blood (a mixture of red blood cells, white blood cells, and platelets) and vascular system (veins, venules, capillaries, arterioles, and arteries), including highly vascularized tissues (e.g. alveoli and glomeruli).
Khandelwal further teaches that IgM facilitates complement and antigen deposition on B cells in vitro and in patients receiving heparin, and anti-C1q antibody prevents IgM-mediated complement activation by PF4/heparin complexes, indicating classical pathway involvement. Thus, polyreactive IgM binds PF4/heparin, triggers activation of the classical complement pathway, and promotes antigen and complement deposition on B cells, leading to the development of antigen-specific antibodies that mediate heparin-induced thrombocytopenia (HIT) (Abstract and Discussion).
Arepally further teaches that, following formation of antibodies to PF4/heparin complexes, a subset of seropositive patients develops thrombocytopenia and can progress to life-threatening thrombotic complications, i.e. HIT with thrombosis (HITT). In particular, the binding of HIT antibodies to platelet FcγRIIA induces platelet activation and is accompanied by robust thrombin generation, thereby contributing to the thrombotic complications of HIT.
It would have been obvious to one of ordinary skill in the art to administer the anti-C1q antibody of the issued claims to a subject having HIT or HITT according to the methods of treating a complement associated disorder taught by Rosenthal. One of ordinary skill in the art would have been motivated to do so because anti-C1q antibodies administered, e.g., by infusion or intravenously, can be used to treat or prevent complement-mediated disorders as taught by Rosenthal; and polyreactive IgM antibodies initiate classical complement activation in response to PF4/heparin complexes, which can contribute to the development of HIT as taught by Khandelwal. In a subset of patients, HIT can be accompanied by thrombotic complications, termed HITT, as taught by Arepally. Because PF4/heparin complexes are implicated in the pathogenesis of HIT/HITT, one of ordinary skill in the art would have reasonably expected for administration of the anti-C1q antibody of the issued claims to inhibit the complement-mediated processes associated with HIT and thereby reduce the occurrence of at least some of its pathological symptoms, including thrombosis that occurs in HITT. Of note, the wherein clauses of the instant claims that recite that C1q selective inhibition “spares C1q activity outside the subject’s blood space” and “reduces tissue damage in highly vascularized tissues” are intended results of the claimed method that do not carry patentable weight. As such, the anti-C1q antibody and method of treatment disclosed by the combined teachings of issued claims and prior art are not patentably distinct from the instantly claimed method.
Claims 1, 20, 21, 24, 76, 77, and 79-87 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11999779B2 in view of Khandelwal et al (Khandelwal, Sanjay, et al. "Polyreactive IgM initiates complement activation by PF4/heparin complexes through the classical pathway." Blood, The Journal of the American Society of Hematology 132.23 (2018): 2431-2440), hereinafter Khandelwal, and Arepally et al Arepally, Gowthami M. "Heparin-induced thrombocytopenia." Blood, The Journal of the American Society of Hematology 129.21 (2017): 2864-2872), hereinafter Arepally.
The issued claims recite a method of treating a disease associated with C1q mediated activation of the classical complement pathway in a subject in need thereof, comprising administering an antibody Fab fragment that binds to C1q and comprises the VH and VL chains of SEQ ID NOs: 1 and 2, corresponding to SEQ ID NOs: 39 and 40 of the instant claims, wherein the antibody Fab fragment is humanized and the disease associated with C1q mediated activation (issued claims 6, 13, 14, 15, and 19). The minimal structure required for the anti-C1q Fab to possess the functional properties set forth in the claims—selective C1q inhibition within the subject’s blood space, shorter half-life relative to a full-length antibody, and rapid clearance—are the heavy and light chain CDRs recited in instant claim 1. As such, the anti-C1q Fab of the issued claims having the same structure possess the functional properties recited in the instant claims.
The issued claims do not recite that the C1q mediated disorder is heparin-induced thrombocytopenia (HIT)/heparin-induced thrombocytopenia and thrombosis (HITT). Further, the issued claims do not recite routes of administration of the anti-C1q Fab.
However, Rosenthal discloses a method of treating or preventing a disease associated with complement activation – such as autoimmune hemolytic anemias— in a subject comprising administering an anti-C1q antibody to the subject (Abstract, Brief Summary: Para. 0021-0023, in particular, and Para. 0229). An individual is successfully "treated", for example, if one or more symptoms associated with a particular disease, disorder, or condition are mitigated or eliminated (Para. 0042).The anti-C1q antibody can be administered by infusion or intravenous, intramuscular, or subcutaneous routes (Para. 0220). Infusion/intravenous administration, e.g. necessarily introduces the anti-C1q antibody or Fab fragment into the circulation for distribution through the blood (a mixture of red blood cells, white blood cells, and platelets) and vascular system (veins, venules, capillaries, arterioles, and arteries), including highly vascularized tissues (e.g. alveoli and glomeruli).
Khandelwal further teaches that IgM facilitates complement and antigen deposition on B cells in vitro and in patients receiving heparin, and anti-C1q antibody prevents IgM-mediated complement activation by PF4/heparin complexes, indicating classical pathway involvement. Thus, polyreactive IgM binds PF4/heparin, triggers activation of the classical complement pathway, and promotes antigen and complement deposition on B cells, leading to the development of antigen-specific antibodies that mediate heparin-induced thrombocytopenia (HIT) (Abstract and Discussion).
Arepally further teaches that, following formation of antibodies to PF4/heparin complexes, a subset of seropositive patients develops thrombocytopenia and can progress to life-threatening thrombotic complications, i.e. HIT with thrombosis (HITT). In particular, the binding of HIT antibodies to platelet FcγRIIA induces platelet activation and is accompanied by robust thrombin generation, thereby contributing to the thrombotic complications of HIT.
It would have been obvious to one of ordinary skill in the art to administer the anti-C1q antibody of the issued claims to a subject having HIT or HITT. One of ordinary skill in the art would have been motivated to do so because anti-C1q antibodies administered, e.g., by infusion or intravenously, can be used to treat or prevent complement-mediated disorders as taught by the issued claims and Rosenthal; and polyreactive IgM antibodies initiate classical complement activation in response to PF4/heparin complexes, which can contribute to the development of HIT as taught by Khandelwal. In a subset of patients, HIT can be accompanied by thrombotic complications, termed HITT, as taught by Arepally. Because PF4/heparin complexes are implicated in the pathogenesis of HIT/HITT, one of ordinary skill in the art would have reasonably expected for administration of the anti-C1q antibody of the co-pending claims to inhibit the complement-mediated processes associated with HIT and thereby reduce the occurrence of at least some of its pathological symptoms, including thrombosis that occurs in HITT. Of note, the wherein clauses of the instant claims that recite that C1q selective inhibition “spares C1q activity outside the subject’s blood space” and “reduces tissue damage in highly vascularized tissues” are intended results of the claimed method that do not carry patentable weight. As such, the anti-C1q antibody and method of treatment disclosed by the combined teachings of the issued claims and prior art are not patentably distinct from the instantly claimed method.
Claims 1, 20, 21, 76, 77, and 79-87 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 9708394B2 in view of Rosenthal (WO2016073685A1, of record), hereinafter Rosenthal, Khandelwal et al (Khandelwal, Sanjay, et al. "Polyreactive IgM initiates complement activation by PF4/heparin complexes through the classical pathway." Blood, The Journal of the American Society of Hematology 132.23 (2018): 2431-2440), hereinafter Khandelwal, and Arepally et al Arepally, Gowthami M. "Heparin-induced thrombocytopenia." Blood, The Journal of the American Society of Hematology 129.21 (2017): 2864-2872), hereinafter Arepally.
The issued claims recite an anti-C1q antibody comprising the VH and VL chains of SEQ ID NOs: 4 and 8, corresponding to SEQ ID NOs: 4 and 8 of the instant claims and fully comprising the CDRs of SEQ ID NOs: 5, 6, 7, 9, 10, and 11, wherein the antibody is a murine, humanized, or chimeric antibody or the antibody is an antigen-binding fragment such as Fab fragments (issued claims 1-5). The minimal structure required for the anti-C1q Fab to possess the functional properties set forth in the claims—selective C1q inhibition within the subject’s blood space, shorter half-life relative to a full-length antibody, and rapid clearance—are the heavy and light chain CDRs recited in instant claim 1. As such, the anti-C1q Fab of the issued claims having the same structure possess the functional properties recited in the instant claims.
The issued claims do not recite a method of treating, reducing the risk of developing, or preventing a blood disorder recited in the claims, such as heparin-induced thrombocytopenia (HIT)/heparin-induced thrombocytopenia and thrombosis (HITT). Further, the issued claims do not recite routes of administration of the anti-C1q Fab.
However, Rosenthal discloses a method of treating or preventing a disease associated with complement activation – such as autoimmune hemolytic anemias— in a subject comprising administering an anti-C1q antibody to the subject (Abstract, Brief Summary: Para. 0021-0023, in particular, and Para. 0229). Prevention includes providing prophylaxis with respect to occurrence or recurrence of a particular disease, disorder, or condition in an individual, including at risk individuals (Para. 0040) whereas an individual is successfully "treated", for example, if one or more symptoms associated with a particular disease, disorder, or condition are mitigated or eliminated (Para. 0042). The anti-C1q antibody can be administered by infusion or intravenous, intramuscular, or subcutaneous routes (Para. 0220). Infusion/intravenous administration, e.g. necessarily introduces the anti-C1q antibody or Fab fragment into the circulation for distribution through the blood (a mixture of red blood cells, white blood cells, and platelets) and vascular system (veins, venules, capillaries, arterioles, and arteries), including highly vascularized tissues (e.g. alveoli and glomeruli).
The issued claims do not recite a method of treating, reducing the risk of developing, or preventing a blood disorder recited in the claims, such as heparin-induced thrombocytopenia (HIT)/heparin-induced thrombocytopenia and thrombosis (HITT).
However, Rosenthal discloses a method of treating or preventing a disease associated with complement activation – such as autoimmune hemolytic anemias— in a subject comprising administering an anti-C1q antibody to the subject (Abstract, Brief Summary: Para. 0021-0023, in particular, and Para. 0229). An individual is successfully "treated", for example, if one or more symptoms associated with a particular disease, disorder, or condition are mitigated or eliminated (Para. 0042).The anti-C1q antibody can be administered by infusion or intravenous, intramuscular, or subcutaneous routes (Para. 0220).
Khandelwal further teaches that IgM facilitates complement and antigen deposition on B cells in vitro and in patients receiving heparin, and anti-C1q antibody prevents IgM-mediated complement activation by PF4/heparin complexes, indicating classical pathway involvement. Thus, polyreactive IgM binds PF4/heparin, triggers activation of the classical complement pathway, and promotes antigen and complement deposition on B cells, leading to the development of antigen-specific antibodies that mediate heparin-induced thrombocytopenia (HIT) (Abstract and Discussion).
Arepally further teaches that, following formation of antibodies to PF4/heparin complexes, a subset of seropositive patients develops thrombocytopenia and can progress to life-threatening thrombotic complications, i.e. HIT with thrombosis (HITT). In particular, the binding of HIT antibodies to platelet FcγRIIA induces platelet activation and is accompanied by robust thrombin generation, thereby contributing to the thrombotic complications of HIT.
It would have been obvious to one of ordinary skill in the art to administer the anti-C1q antibody of the issued claims to a subject having HIT or HITT according to the methods of treating a complement associated disorder taught by Rosenthal. One of ordinary skill in the art would have been motivated to do so because anti-C1q antibodies administered, e.g., by infusion or intravenously, can be used to treat or prevent complement-mediated disorders as taught by Rosenthal; and polyreactive IgM antibodies initiate classical complement activation in response to PF4/heparin complexes, which can contribute to the development of HIT as taught by Khandelwal. In a subset of patients, HIT can be accompanied by thrombotic complications, termed HITT, as taught by Arepally. Because PF4/heparin complexes are implicated in the pathogenesis of HIT/HITT, one of ordinary skill in the art would have reasonably expected for administration of the anti-C1q antibody of the issued claims to inhibit the complement-mediated processes associated with HIT and thereby reduce the occurrence of at least some of its pathological symptoms, including thrombosis, as they occur in HITT. Of note, the wherein clauses of the instant claims that recite that C1q selective inhibition “spares C1q activity outside the subject’s blood space” and “reduces tissue damage in highly vascularized tissues” are intended results of the claimed method that do not carry patentable weight. As such, the anti-C1q antibody and method of treatment disclosed by the combined teachings of the issued claims and prior art are not patentably distinct from the instantly claimed method.
Claim 24 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 9708394B2 in view of Rosenthal, Khandelwal and Arepally, as applied to claims 1, 20, 21, 76, 77, and 79-87 above, and further in view of Yednock et al (US20170152309A1, of record), hereinafter Yednock.
The teachings of the issued claims in view of Rosenthal, Khandelwal and Arepally have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-C1q Fab fragment comprises heavy and light chains of SEQ ID NOs: 39 and 40, respectively.
However, Yednock discloses a method of treating or preventing a disease associated with complement activation in a subject comprising administering an anti-C1q antibody Fab fragment to the subject, wherein the anti-C1q Fab fragment has the heavy and lights chains set forth in SEQ ID NOs: 1 and 2, respectively (corresponding to SEQ ID NOs: 39 and 40 of the instant claims). It would have been obvious to modify the method of treating or preventing a complement associated disorder subject disclosed by the issued claims such that the anti-C1q Fab fragment is substituted with that of Yednock having the heavy and light chains of SEQ ID NOs: 1 and 2. One of ordinary skill in the art would have been motivated to do so since the anti-C1q Fab fragments of the issued claims and Yednock 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). Therefore one of ordinary skill in the art would reasonably expect for administration of the anti-C1q Fab fragment disclosed by Yednock to inhibit the complement-mediated processes associated with HIT and thereby reduce the occurrence of at least some of its pathological smptoms, including thrombosis, as they occur in HITT.
Claims 1, 20, 21, 76, 77, and 79-87 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 10227398B2 in view of Khandelwal et al (Khandelwal, Sanjay, et al. "Polyreactive IgM initiates complement activation by PF4/heparin complexes through the classical pathway." Blood, The Journal of the American Society of Hematology 132.23 (2018): 2431-2440), hereinafter Khandelwal, and Arepally et al Arepally, Gowthami M. "Heparin-induced thrombocytopenia." Blood, The Journal of the American Society of Hematology 129.21 (2017): 2864-2872), hereinafter Arepally.
The issued claims recite a method of treating a disease associated with C1q mediated complement activation comprising administering a therapeutically effective dose of an anti-C1q antibody comprising the VH and VL chains of SEQ ID NOs: 4 and 8, corresponding to SEQ ID NOs: 4 and 8 of the instant claims and fully comprising the CDRs of SEQ ID NOs: 5, 6, 7, 9, 10, and 11 (issued claims 1, 8, 9, 10, 11, 12, and 20). The antibody is an antigen-binding fragment such as a Fab fragment (issued claims 19, 23, 24, and 25). The minimal structure required for the anti-C1q Fab to possess the functional properties set forth in the claims—selective C1q inhibition within the subject’s blood space, shorter half-life relative to a full-length antibody, and rapid clearance—are the heavy and light chain CDRs recited in instant claim 1. As such, the anti-C1q Fab of the issued claims having the same structure possess the functional properties recited in the instant claims.
The issued claims do not recite a method of treating, reducing the risk of developing, or preventing a blood disorder recited in the claims, such as heparin-induced thrombocytopenia (HIT)/heparin-induced thrombocytopenia and thrombosis (HITT). Further, the issued claims do not recite routes of administration of the anti-C1q Fab.
However, Rosenthal discloses a method of treating or preventing a disease associated with complement activation – such as autoimmune hemolytic anemias— in a subject comprising administering an anti-C1q antibody to the subject (Abstract, Brief Summary: Para. 0021-0023, in particular, and Para. 0229). Prevention includes providing prophylaxis with respect to occurrence or recurrence of a particular disease, disorder, or condition in an individual, including at risk individuals (Para. 0040) whereas an individual is successfully "treated", for example, if one or more symptoms associated with a particular disease, disorder, or condition are mitigated or eliminated (Para. 0042). The anti-C1q antibody can be administered by infusion or intravenous, intramuscular, or subcutaneous routes (Para. 0220). Infusion/intravenous administration, e.g. necessarily introduces the anti-C1q antibody or Fab fragment into the circulation for distribution through the blood (a mixture of red blood cells, white blood cells, and platelets) and vascular system (veins, venules, capillaries, arterioles, and arteries), including highly vascularized tissues (e.g. alveoli and glomeruli).
Khandelwal further teaches that IgM facilitates complement and antigen deposition on B cells in vitro and in patients receiving heparin, and anti-C1q antibody prevents IgM-mediated complement activation by PF4/heparin complexes, indicating classical pathway involvement. Thus, polyreactive IgM binds PF4/heparin, triggers activation of the classical complement pathway, and promotes antigen and complement deposition on B cells, leading to the development of antigen-specific antibodies that mediate heparin-induced thrombocytopenia (HIT) (Abstract and Discussion).
Arepally further teaches that, following formation of antibodies to PF4/heparin complexes, a subset of seropositive patients develops thrombocytopenia and can progress to life-threatening thrombotic complications, i.e. HIT with thrombosis (HITT). In particular, the binding of HIT antibodies to platelet FcγRIIA induces platelet activation and is accompanied by robust thrombin generation, thereby contributing to the thrombotic complications of HIT.
It would have been obvious to one of ordinary skill in the art to administer the anti-C1q antibody of the issued claims to a subject having HIT or HITT. One of ordinary skill in the art would have been motivated to do so because anti-C1q antibodies administered, e.g., by infusion or intravenously, can be used to treat or prevent complement-mediated disorders as taught by the issued claims and Rosenthal; and polyreactive IgM antibodies initiate classical complement activation in response to PF4/heparin complexes, which can contribute to the development of HIT as taught by Khandelwal. In a subset of patients, HIT can be accompanied by thrombotic complications, termed HITT, as taught by Arepally. Because PF4/heparin complexes are implicated in the pathogenesis of HIT/HITT, one of ordinary skill in the art would have reasonably expected for administration of the anti-C1q antibody of the co-pending claims to inhibit the complement-mediated processes associated with HIT and thereby reduce the occurrence of at least some of its pathological consequences, including thrombosis, as they occur in HITT. Of note, the wherein clauses of the instant claims that recite that C1q selective inhibition “spares C1q activity outside the subject’s blood space” and “reduces tissue damage in highly vascularized tissues” are intended results of the claimed method that do not carry patentable weight. As such, the anti-C1q antibody and method of treatment disclosed by the combined teachings of the issued claims and prior art are not patentably distinct from the instantly claimed method.
Claim 24 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 10227398B2 in view of Khandelwal and Arepally, as applied to claims 1, 20, 21, 76, 77, and 79-87 above, and further in view of Yednock et al (US20170152309A1, of record), hereinafter Yednock.
The teachings of the copending claims in view of Khandelwal and Arepally have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-C1q Fab fragment comprises heavy and light chains of SEQ ID NOs: 39 and 40, respectively.
However, Yednock discloses a method of treating or preventing a disease associated with complement activation in a subject comprising administering an anti-C1q antibody Fab fragment to the subject, wherein the anti-C1q Fab fragment has the heavy and lights chains set forth in SEQ ID NOs: 1 and 2, respectively (corresponding to SEQ ID NOs: 39 and 40 of the instant claims). It would have been obvious to modify the method of treating or preventing a complement associated disorder subject disclosed by the issued claims such that the anti-C1q Fab fragment is substituted with that of Yednock having the heavy and light chains of SEQ ID NOs: 1 and 2. One of ordinary skill in the art would have been motivated to do so since the anti-C1q Fab fragments of issued claims and Yednock 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). Therefore one of ordinary skill in the art would reasonably expect for administration of the anti-C1q Fab fragment disclosed by Yednock to inhibit the complement-mediated processes associated with HIT and thereby reduce the occurrence of at least some of its pathological consequences, including thrombosis, as they occur in HITT.
Claims 1, 20, 21, 76, 77, and 79-87 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 10590190B2 in view of Rosenthal (WO2016073685A1, of record), hereinafter Rosenthal, Khandelwal et al (Khandelwal, Sanjay, et al. "Polyreactive IgM initiates complement activation by PF4/heparin complexes through the classical pathway." Blood, The Journal of the American Society of Hematology 132.23 (2018): 2431-2440), hereinafter Khandelwal, and Arepally et al Arepally, Gowthami M. "Heparin-induced thrombocytopenia." Blood, The Journal of the American Society of Hematology 129.21 (2017): 2864-2872), hereinafter Arepally.
The issued claims recite an anti-C1q antibody comprising the VH and VL chains of SEQ ID NOs: 4 and 8, corresponding to SEQ ID NOs: 4 and 8 of the instant claims and fully comprising the CDRs of SEQ ID NOs: 5, 6, 7, 9, 10, and 11, (issued claims 1-7). The antibody is a murine, humanized, or chimeric antibody or the antibody is an antigen-binding fragment such as Fab, F(ab’)2, or Fab’ fragments (issued claims 16, 19, and 20). The minimal structure required for the anti-C1q Fab to possess the functional properties set forth in the claims—selective C1q inhibition within the subject’s blood space, shorter half-life relative to a full-length antibody, and rapid clearance—are the heavy and light chain CDRs recited in instant claim 1. As such, the anti-C1q Fab of the issued claims having the same structure possess the functional properties recited in the instant claims.
The issued claims do not recite a method of treating, reducing the risk of developing, or preventing a blood disorder recited in the claims, such as heparin-induced thrombocytopenia (HIT)/heparin-induced thrombocytopenia and thrombosis (HITT). Further, the issued claims do not recite routes of administration of the anti-C1q Fab.
However, Rosenthal discloses a method of treating or preventing a disease associated with complement activation – such as autoimmune hemolytic anemias— in a subject comprising administering an anti-C1q antibody to the subject (Abstract, Brief Summary: Para. 0021-0023, in particular, and Para. 0229). Prevention includes providing prophylaxis with respect to occurrence or recurrence of a particular disease, disorder, or condition in an individual, including at risk individuals (Para. 0040) whereas an individual is successfully "treated", for example, if one or more symptoms associated with a particular disease, disorder, or condition are mitigated or eliminated (Para. 0042). The anti-C1q antibody can be administered by infusion or intravenous, intramuscular, or subcutaneous routes (Para. 0220). Infusion/intravenous administration, e.g. necessarily introduces the anti-C1q antibody or Fab fragment into the circulation for distribution through the blood (a mixture of red blood cells, white blood cells, and platelets) and vascular system (veins, venules, capillaries, arterioles, and arteries), including highly vascularized tissues (e.g. alveoli and glomeruli).
Khandelwal further teaches that IgM facilitates complement and antigen deposition on B cells in vitro and in patients receiving heparin, and anti-C1q antibody prevents IgM-mediated complement activation by PF4/heparin complexes, indicating classical pathway involvement. Thus, polyreactive IgM binds PF4/heparin, triggers activation of the classical complement pathway, and promotes antigen and complement deposition on B cells, leading to the development of antigen-specific antibodies that mediate heparin-induced thrombocytopenia (HIT) (Abstract and Discussion).
Arepally further teaches that, following formation of antibodies to PF4/heparin complexes, a subset of seropositive patients develops thrombocytopenia and can progress to life-threatening thrombotic complications, i.e. HIT with thrombosis (HITT). In particular, the binding of HIT antibodies to platelet FcγRIIA induces platelet activation and is accompanied by robust thrombin generation, thereby contributing to the thrombotic complications of HIT.
It would have been obvious to one of ordinary skill in the art to administer the anti-C1q antibody of the issued claims to a subject having HIT or HITT according to the methods of treating a complement associated disorder taught by Rosenthal. One of ordinary skill in the art would have been motivated to do so because anti-C1q antibodies administered, e.g., by infusion or intravenously, can be used to treat or prevent complement-mediated disorders as taught by the issued claims and Rosenthal; and polyreactive IgM antibodies initiate classical complement activation in response to PF4/heparin complexes, which can contribute to the development of HIT as taught by Khandelwal. In a subset of patients, HIT can be accompanied by thrombotic complications, termed HITT, as taught by Arepally. Because PF4/heparin complexes are implicated in the pathogenesis of HIT/HITT, one of ordinary skill in the art would have reasonably expected for administration of the anti-C1q antibody of the issued claims to inhibit the complement-mediated processes associated with HIT and thereby reduce the occurrence of at least some of its pathological consequences, including thrombosis, as they occur in HITT. Of note, the wherein clauses of the instant claims that recite that C1q selective inhibition “spares C1q activity outside the subject’s blood space” and “reduces tissue damage in highly vascularized tissues” are intended results of the claimed method that do not carry patentable weight. As such, the anti-C1q antibody and method of treatment disclosed by the combined teachings of the issued claims and prior art are not patentably distinct from the instantly claimed method.
Claim 24 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 10590190B2 in view of Rosenthal, Khandelwal and Arepally, as applied to claims 1, 20, 21, 76, 77, and 79-87 above, and further in view of Yednock et al (US20170152309A1, of record), hereinafter Yednock.
The teachings of the issued claims in view of Rosenthal, Khandelwal and Arepally have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-C1q Fab fragment comprises heavy and light chains of SEQ ID NOs: 39 and 40, respectively.
However, Yednock discloses a method of treating or preventing a disease associated with complement activation in a subject comprising administering an anti-C1q antibody Fab fragment to the subject, wherein the anti-C1q Fab fragment has the heavy and lights chains set forth in SEQ ID NOs: 1 and 2, respectively (corresponding to SEQ ID NOs: 39 and 40 of the instant claims). It would have been obvious to modify the method of treating or preventing a complement associated disorder subject disclosed by the issued claims such that the anti-C1q Fab fragment is substituted with that of Yednock having the heavy and light chains of SEQ ID NOs: 1 and 2. One of ordinary skill in the art would have been motivated to do so since the anti-C1q Fab fragments of issued claims and Yednock 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). Therefore one of ordinary skill in the art would reasonably expect for administration of the anti-C1q Fab fragment disclosed by Yednock to inhibit the complement-mediated processes associated with HIT and thereby reduce the occurrence of at least some of its pathological consequences, including thrombosis, as they occur in HITT.
Claims 1, 20, 21, 76, 77, and 79-87 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 10927167B2 in view of Rosenthal (WO2016073685A1, of record), hereinafter Rosenthal, Khandelwal et al (Khandelwal, Sanjay, et al. "Polyreactive IgM initiates complement activation by PF4/heparin complexes through the classical pathway." Blood, The Journal of the American Society of Hematology 132.23 (2018): 2431-2440), hereinafter Khandelwal, and Arepally et al Arepally, Gowthami M. "Heparin-induced thrombocytopenia." Blood, The Journal of the American Society of Hematology 129.21 (2017): 2864-2872), hereinafter Arepally.
The issued claims recite an anti-C1q antibody comprising the VH and VL chains of SEQ ID NOs: 4 and 8, corresponding to SEQ ID NOs: 4 and 8 of the instant claims and fully comprising the CDRs of SEQ ID NOs: 5, 6, 7, 9, 10, and 11, (issued claims 1-19). The antibody is a murine, humanized, or chimeric antibody (issued claim 10). Further recited is a kit comprising the anti-C1q antibody and instructions for use in treating or preventing a disease associated with complement activation in an individual (issued claim 13). The minimal structure required for the anti-C1q Fab to possess the functional properties set forth in the claims—selective C1q inhibition within the subject’s blood space, shorter half-life relative to a full-length antibody, and rapid clearance—are the heavy and light chain CDRs recited in instant claim 1. As such, the anti-C1q Fab of the issued claims having the same structure possess the functional properties recited in the instant claims.
The issued claims do not recite a method of treating, reducing the risk of developing, or preventing a blood disorder recited in the claims, such as heparin-induced thrombocytopenia (HIT)/heparin-induced thrombocytopenia and thrombosis (HITT). Further, the issued claims do not recite routes of administration of the anti-C1q Fab.
However, Rosenthal discloses a method of treating or preventing a disease associated with complement activation – such as autoimmune hemolytic anemias— in a subject comprising administering an anti-C1q antibody to the subject (Abstract, Brief Summary: Para. 0021-0023, in particular, and Para. 0229). Prevention includes providing prophylaxis with respect to occurrence or recurrence of a particular disease, disorder, or condition in an individual, including at risk individuals (Para. 0040) whereas an individual is successfully "treated", for example, if one or more symptoms associated with a particular disease, disorder, or condition are mitigated or eliminated (Para. 0042). anti-C1q antibody can be administered by infusion or intravenous, intramuscular, or subcutaneous routes (Para. 0220). Infusion/intravenous administration, e.g. necessarily introduces the anti-C1q antibody or Fab fragment into the circulation for distribution through the blood (a mixture of red blood cells, white blood cells, and platelets) and vascular system (veins, venules, capillaries, arterioles, and arteries), including highly vascularized tissues (e.g. alveoli and glomeruli).
Khandelwal further teaches that IgM facilitates complement and antigen deposition on B cells in vitro and in patients receiving heparin, and anti-C1q antibody prevents IgM-mediated complement activation by PF4/heparin complexes, indicating classical pathway involvement. Thus, polyreactive IgM binds PF4/heparin, triggers activation of the classical complement pathway, and promotes antigen and complement deposition on B cells, leading to the development of antigen-specific antibodies that mediate heparin-induced thrombocytopenia (HIT) (Abstract and Discussion).
Arepally further teaches that, following formation of antibodies to PF4/heparin complexes, a subset of seropositive patients develops thrombocytopenia and can progress to life-threatening thrombotic complications, i.e. HIT with thrombosis (HITT). In particular, the binding of HIT antibodies to platelet FcγRIIA induces platelet activation and is accompanied by robust thrombin generation, thereby contributing to the thrombotic complications of HIT.
It would have been obvious to one of ordinary skill in the art to administer the anti-C1q antibody of the issued claims to a subject having HIT or HITT according to the methods of treating a complement associated disorder taught by Rosenthal. One of ordinary skill in the art would have been motivated to do so because anti-C1q antibodies administered, e.g., by infusion or intravenously, can be used to treat or prevent complement-mediated disorders as taught by Rosenthal; and polyreactive IgM antibodies initiate classical complement activation in response to PF4/heparin complexes, which can contribute to the development of HIT as taught by Khandelwal. In a subset of patients, HIT can be accompanied by thrombotic complications, termed HITT, as taught by Arepally. Because PF4/heparin complexes are implicated in the pathogenesis of HIT/HITT, one of ordinary skill in the art would have reasonably expected for administration of the anti-C1q antibody of the issued claims to inhibit the complement-mediated processes associated with HIT and thereby reduce the occurrence of at least some of its pathological consequences, including thrombosis, as they occur in HITT. Of note, the wherein clauses of the instant claims that recite that C1q selective inhibition “spares C1q activity outside the subject’s blood space” and “reduces tissue damage in highly vascularized tissues” are intended results of the claimed method that do not carry patentable weight. As such, the anti-C1q antibody and method of treatment disclosed by the combined teachings of the issued claims and prior art are not patentably distinct from the instantly claimed method.
Claim 24 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 10927167B2 in view of Rosenthal, Khandelwal and Arepally, as applied to claims 1, 20, 21, 76, 77, and 79-87 above, and further in view of Yednock et al (US20170152309A1, of record), hereinafter Yednock.
The teachings of the issued claims in view of Rosenthal, Khandelwal and Arepally have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-C1q Fab fragment comprises heavy and light chains of SEQ ID NOs: 39 and 40, respectively.
However, Yednock discloses a method of treating or preventing a disease associated with complement activation in a subject comprising administering an anti-C1q antibody Fab fragment to the subject, wherein the anti-C1q Fab fragment has the heavy and lights chains set forth in SEQ ID NOs: 1 and 2, respectively (corresponding to SEQ ID NOs: 39 and 40 of the instant claims). It would have been obvious to modify the method of treating or preventing a complement associated disorder subject disclosed by the issued claims such that the anti-C1q Fab fragment is substituted with that of Yednock having the heavy and light chains of SEQ ID NOs: 1 and 2. One of ordinary skill in the art would have been motivated to do so since the anti-C1q Fab fragments of the issued claims and Yednock 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). Therefore one of ordinary skill in the art would reasonably expect for administration of the anti-C1q Fab fragment disclosed by Yednock to inhibit the complement-mediated processes associated with HIT and thereby reduce the occurrence of at least some of its pathological consequences, including thrombosis, as they occur in HITT.
Claims 1, 20, 21, 76, 77, and 79-87 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 11649279B2 in view of Rosenthal (WO2016073685A1, of record), hereinafter Rosenthal, Khandelwal et al (Khandelwal, Sanjay, et al. "Polyreactive IgM initiates complement activation by PF4/heparin complexes through the classical pathway." Blood, The Journal of the American Society of Hematology 132.23 (2018): 2431-2440), hereinafter Khandelwal, and Arepally et al Arepally, Gowthami M. "Heparin-induced thrombocytopenia." Blood, The Journal of the American Society of Hematology 129.21 (2017): 2864-2872), hereinafter Arepally.
The issued claims recite an anti-C1q antibody comprising the VH and VL chains of SEQ ID NOs: 4 and 8, corresponding to SEQ ID NOs: 4 and 8 of the instant claims and fully comprising the CDRs of SEQ ID NOs: 5, 6, 7, 9, 10, and 11, (issued claims 1-21). The antibody is an antibody fragment such as Fab (issued claims 16, 19, and 20). The minimal structure required for the anti-C1q Fab to possess the functional properties set forth in the claims—selective C1q inhibition within the subject’s blood space, shorter half-life relative to a full-length antibody, and rapid clearance—are the heavy and light chain CDRs recited in instant claim 1. As such, the anti-C1q Fab of the issued claims having the same structure possess the functional properties recited in the instant claims.
The issued claims do not recite a method of treating, reducing the risk of developing, or preventing a blood disorder recited in the claims, such as heparin-induced thrombocytopenia (HIT)/heparin-induced thrombocytopenia and thrombosis (HITT). Further, the issued claims do not recite routes of administration of the anti-C1q Fab.
However, Rosenthal discloses a method of treating or preventing a disease associated with complement activation – such as autoimmune hemolytic anemias— in a subject comprising administering an anti-C1q antibody to the subject (Abstract, Brief Summary: Para. 0021-0023, in particular, and Para. 0229). Prevention includes providing prophylaxis with respect to occurrence or recurrence of a particular disease, disorder, or condition in an individual, including at risk individuals (Para. 0040) whereas an individual is successfully "treated", for example, if one or more symptoms associated with a particular disease, disorder, or condition are mitigated or eliminated (Para. 0042). The anti-C1q antibody can be administered by infusion or intravenous, intramuscular, or subcutaneous routes (Para. 0220). Infusion/intravenous administration, e.g. necessarily introduces the anti-C1q antibody or Fab fragment into the circulation for distribution through the blood (a mixture of red blood cells, white blood cells, and platelets) and vascular system (veins, venules, capillaries, arterioles, and arteries), including highly vascularized tissues (e.g. alveoli and glomeruli).
Khandelwal further teaches that IgM facilitates complement and antigen deposition on B cells in vitro and in patients receiving heparin, and anti-C1q antibody prevents IgM-mediated complement activation by PF4/heparin complexes, indicating classical pathway involvement. Thus, polyreactive IgM binds PF4/heparin, triggers activation of the classical complement pathway, and promotes antigen and complement deposition on B cells, leading to the development of antigen-specific antibodies that mediate heparin-induced thrombocytopenia (HIT) (Abstract and Discussion).
Arepally further teaches that, following formation of antibodies to PF4/heparin complexes, a subset of seropositive patients develops thrombocytopenia and can progress to life-threatening thrombotic complications, i.e. HIT with thrombosis (HITT). In particular, the binding of HIT antibodies to platelet FcγRIIA induces platelet activation and is accompanied by robust thrombin generation, thereby contributing to the thrombotic complications of HIT.
It would have been obvious to one of ordinary skill in the art to administer the anti-C1q antibody of the issued claims to a subject having HIT or HITT according to the methods of treating a complement associated disorder taught by Rosenthal. One of ordinary skill in the art would have been motivated to do so because anti-C1q antibodies administered, e.g., by infusion or intravenously, can be used to treat or prevent complement-mediated disorders as taught by Rosenthal; and polyreactive IgM antibodies initiate classical complement activation in response to PF4/heparin complexes, which can contribute to the development of HIT as taught by Khandelwal. In a subset of patients, HIT can be accompanied by thrombotic complications, termed HITT, as taught by Arepally. Because PF4/heparin complexes are implicated in the pathogenesis of HIT/HITT, one of ordinary skill in the art would have reasonably expected for administration of the anti-C1q antibody of the issued claims to inhibit the complement-mediated processes associated with HIT and thereby reduce the occurrence of at least some of its pathological consequences, including thrombosis, as they occur in HITT. Of note, the wherein clauses of the instant claims that recite that C1q selective inhibition “spares C1q activity outside the subject’s blood space” and “reduces tissue damage in highly vascularized tissues” are intended results of the claimed method that do not carry patentable weight. As such, the anti-C1q antibody and method of treatment disclosed by the combined teachings of the issued claims and prior art are not patentably distinct from the instantly claimed method.
Claim 24 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 11649279B2 in view of Rosenthal, Khandelwal and Arepally, as applied to claims 1, 20, 21, 76, 77, and 79-87 above, and further in view of Yednock et al (US20170152309A1, of record), hereinafter Yednock.
The teachings of the issued claims in view of Rosenthal, Khandelwal and Arepally have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-C1q Fab fragment comprises heavy and light chains of SEQ ID NOs: 39 and 40, respectively.
However, Yednock discloses a method of treating or preventing a disease associated with complement activation in a subject comprising administering an anti-C1q antibody Fab fragment to the subject, wherein the anti-C1q Fab fragment has the heavy and lights chains set forth in SEQ ID NOs: 1 and 2, respectively (corresponding to SEQ ID NOs: 39 and 40 of the instant claims). It would have been obvious to modify the method of treating or preventing a complement associated disorder subject disclosed by the issued claims such that the anti-C1q Fab fragment is substituted with that of Yednock having the heavy and light chains of SEQ ID NOs: 1 and 2. One of ordinary skill in the art would have been motivated to do so since the anti-C1q Fab fragments of the issued claims and Yednock 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). Therefore one of ordinary skill in the art would reasonably expect for administration of the anti-C1q Fab fragment disclosed by Yednock to inhibit the complement-mediated processes associated with HIT and thereby reduce the occurrence of at least some of its pathological consequences, including thrombosis, as they occur in HITT.
Claims 1, 20, 21, 76, 77, and 79-87 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10, 12-13, 16, and 23-29 of copending Application No. 18100885 in view of Rosenthal et al (WO2016073685A1, of record), hereinafter Rosenthal, Khandelwal et al (Khandelwal, Sanjay, et al. "Polyreactive IgM initiates complement activation by PF4/heparin complexes through the classical pathway." Blood, The Journal of the American Society of Hematology 132.23 (2018): 2431-2440), hereinafter Khandelwal, and Arepally et al Arepally, Gowthami M. "Heparin-induced thrombocytopenia." Blood, The Journal of the American Society of Hematology 129.21 (2017): 2864-2872), hereinafter Arepally.
This is a provisional nonstatutory double patenting rejection.
The co-pending claims recite a polynucleotide comprising a humanized anti-C1q antibody or antigen-binding fragment thereof comprising the VH chains of SEQ ID NOs: 1-4 (corresponding to SEQ ID NOs: 31-34 of the instant claims) and the VL chains of SEQ ID NOs: 5-8 (corresponding to SEQ ID NOs: 5-8 of the instant claims) (co-pending claim 23). The minimal structure required for the anti-C1q Fab to possess the functional properties set forth in the claims—selective C1q inhibition within the subject’s blood space, shorter half-life relative to a full-length antibody, and rapid clearance—are the heavy and light chain CDRs recited in instant claim 1. As such, the anti-C1q Fab of the co-pending claims having the same structure possess the functional properties recited in the instant claims.
The co-pending claims do not recite a method of treating, reducing the risk of developing, or preventing a blood disorder recited in the claims, such as heparin-induced thrombocytopenia (HIT)/heparin-induced thrombocytopenia and thrombosis (HITT) nor does it recite that the anti-C1q antibody fragment is a Fab fragment.
However, Rosenthal discloses a method of treating or preventing a disease associated with complement activation – such as autoimmune hemolytic anemias— in a subject comprising administering an anti-C1q antibody to the subject (Abstract, Brief Summary: Para. 0021-0023, in particular, and Para. 0229). Prevention includes providing prophylaxis with respect to occurrence or recurrence of a particular disease, disorder, or condition in an individual, including at risk individuals (Para. 0040) whereas an individual is successfully "treated", for example, if one or more symptoms associated with a particular disease, disorder, or condition are mitigated or eliminated (Para. 0042). The anti-C1q antibody can be administered by infusion or intravenous, intramuscular, or subcutaneous routes (Para. 0220). Infusion/intravenous administration, e.g. necessarily introduces the anti-C1q antibody or Fab fragment into the circulation for distribution through the blood (a mixture of red blood cells, white blood cells, and platelets) and vascular system (veins, venules, capillaries, arterioles, and arteries), including highly vascularized tissues (e.g. alveoli and glomeruli).
Khandelwal further teaches that IgM facilitates complement and antigen deposition on B cells in vitro and in patients receiving heparin, and anti-C1q antibody prevents IgM-mediated complement activation by PF4/heparin complexes, indicating classical pathway involvement. Thus, polyreactive IgM binds PF4/heparin, triggers activation of the classical complement pathway, and promotes antigen and complement deposition on B cells, leading to the development of antigen-specific antibodies that mediate heparin-induced thrombocytopenia (HIT) (Abstract and Discussion).
Arepally further teaches that, following formation of antibodies to PF4/heparin complexes, a subset of seropositive patients develops thrombocytopenia and can progress to life-threatening thrombotic complications, i.e. HIT with thrombosis (HITT). In particular, the binding of HIT antibodies to platelet FcγRIIA induces platelet activation and is accompanied by robust thrombin generation, thereby contributing to the thrombotic complications of HIT.
It would have been obvious to one of ordinary skill in the art to administer the anti-C1q antibody of the issued claims to a subject having HIT or HITT. One of ordinary skill in the art would have been motivated to do so because anti-C1q antibodies, including Fab fragments, administered, e.g., by infusion or intravenously, can be used to treat or prevent complement-mediated disorders as taught by the co-pending claims and Rosenthal; and polyreactive IgM antibodies initiate classical complement activation in response to PF4/heparin complexes, which can contribute to the development of HIT as taught by Khandelwal. In a subset of patients, HIT can be accompanied by thrombotic complications, termed HITT, as taught by Arepally. Because PF4/heparin complexes are implicated in the pathogenesis of HIT/HITT, one of ordinary skill in the art would have reasonably expected for administration of the anti-C1q antibody of the co-pending claims to inhibit the complement-mediated processes associated with HIT and thereby reduce the occurrence of at least some of its pathological consequences, including thrombosis, as they occur in HITT. Of note, the wherein clauses of the instant claims that recite that C1q selective inhibition “spares C1q activity outside the subject’s blood space” and “reduces tissue damage in highly vascularized tissues” are intended results of the claimed method that do not carry patentable weight. As such, the anti-C1q antibody and method of treatment disclosed by the combined teachings of the co-pending claims and prior art are not patentably distinct from the instantly claimed method.
Claim 24 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10, 12-13, 16, and 23-29 of copending Application No. 18100885 in view of Rosenthal, Khandelwal and Arepally, as applied to claims 1, 20, 21, 76, 77, and 79-87 above, and further in view of Yednock et al (US20170152309A1, of record), hereinafter Yednock.
The teachings of the co-pending claims in view of Rosenthal, Khandelwal and Arepally have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-C1q Fab fragment comprises heavy and light chains of SEQ ID NOs: 39 and 40, respectively.
However, Yednock discloses a method of treating or preventing a disease associated with complement activation in a subject comprising administering an anti-C1q antibody Fab fragment to the subject, wherein the anti-C1q Fab fragment has the heavy and lights chains set forth in SEQ ID NOs: 1 and 2, respectively (corresponding to SEQ ID NOs: 39 and 40 of the instant claims). It would have been obvious to modify the method of treating or preventing a complement associated disorder subject disclosed by the co-pending claims such that the anti-C1q Fab fragment is substituted with that of Yednock having the heavy and light chains of SEQ ID NOs: 1 and 2. One of ordinary skill in the art would have been motivated to do so since the anti-C1q Fab fragments of the co-pending claims and Yednock 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). Therefore one of ordinary skill in the art would reasonably expect for administration of the anti-C1q Fab fragment disclosed by Yednock to inhibit the complement-mediated processes associated with HIT and thereby reduce the occurrence of at least some of its pathological consequences, including thrombosis, as they occur in HITT.
Response to Arguments
Applicant's arguments filed 03/23/2026 have been fully considered but they are not fully persuasive.
With respect to the 35 USC 112(a) rejection, Applicant argues that “[t]he enablement standard requires only that a person of ordinary skill in the art be able to practice the claimed invention without undue experimentation. Here, the claims define a circumscribed class of blood disorders, those associated with Clq-mediated activation of the classical complement pathway, as mechanistically and clinically described in the specification. The claims further define a structurally characterized Fab fragment with specified CDR sequences, for which the specification provides complete structural, functional, and production details. A skilled artisan, armed with these teachings, could readily and predictably use the recited Fab fragments to treat blood disorders associated with Clq-mediated activation as claimed, without any undue experimentation.”
In particular, Applicant states that the “[e]xamples in the specification provide concrete exemplification in CAD and wAIHA hemolysis systems, in HIT mechanistic assays, and provides PK and PD guidance in primate studies; and argues that 35 USC112(a) does not require a separate working example for every listed disease where, as here, the specification teaches a unifying mechanism of action, provides representative data across multiple species and experimental contexts, and supplies actionable guidance for monitoring, and confirming the claimed functional performance”. Applicant asserts that “[t]he disclosure supplies disease-specific mechanistic evidence where most probative (HIT classical pathway activation by PF4/heparin and its abrogation by anti- Clq), functional ex vivo and in vivo data in CAD and wAIHA, and the pharmacologic framework that realizes blood-space selectivity with Fab fragments”. Further, Applicant argues that “[e]xample 8 details tissue distribution experiments predicting that Fab dosing saturates and inhibits Clq in blood but not in tissues, and this prediction is confirmed by Example 9's exposure results. The pharmacokinetic contrast with full-length antibody is stark and explicit: full-length IgG persists for days, penetrates tissues, and systemically suppresses Clq, whereas Fab fragments have a two-to-three-hour serum half-life with rapid clearance of unbound Fab fragments, which confines functional inhibition to the intravascular compartment (page 17, lines 6-18). The amended claim's express functional feature, selective inhibition in the blood space, sparing Clq outside the blood space, precisely mirrors this demonstrated PK/PD reality”.
Taken together, Applicant contends that these teachings confirm that no undue experimentation would be required to practice the claimed methods across their full scope.
In response to Applicant’s arguments, the Examiner notes that although C1q-mediated activation of the classical complement pathway may contribute to the pathogenesis of certain disorders, the mere occurrence of classical complement activation in infections does not readily establish that that C1q activation contributes to disease pathogenesis nor that C1q inhibition would be therapeutically beneficial. Indeed, the prior art teaches that, during infections, activation of C1q and the classical complement pathway constitutes a normal component of innate immune defense against pathogens (Dunkelberger et al, see Abstract, Complement Origins and Actions, Regulation of Complement Activation, and Effectors of the Complement Systems sections, of record), and C1q deficiency aggravates and/or increases susceptibility to bacterial and viral infections (Schulz et al, see Abstract, Introduction, and Sections 5.1 and 5.3, of record). Moreover, while the specification exemplifies specific disorders associated with C1q-mediated classical complement activation such as CAD, wAIHA, and HIT/HITT, it does not provide sufficient evidence to establish C1q-mediated classical pathway activation as a therapeutic target across every disorder within the broad categories recited, including thromboses, drug-induced hematological disorders, and infections. Indeed, the prior art does not appear to establish as a general rule that classical pathway activation predictably occurs in most, if not all, types of thrombotic and drug-induced hematological disorders. Without further guidance provided in the specification, artisans would necessarily have to engage in undue trial and error experimentation to identify members of these broad categories that are associated with C1q mediated classical pathway activation and for which C1q inhibition would reasonably be expected to provide therapeutic benefit.
Therefore, the 35 USC 112(a) rejection is maintained.
The Examiner further notes that the minimal structure required for the anti-C1q Fab to possess the functional properties set forth in the claims—selective C1q inhibition within the subject’s blood space, shorter half-life relative to a full-length antibody, and rapid clearance—are the heavy and light chain CDRs recited in instant claim 1. As such, the anti-C1q Fab disclosed by the prior art having the same structure possess the functional properties recited in the instant claims. Further, the prior art teaches that the anti-C1q antibody or Fab fragment can be administered, e.g. by infusion/intravenously, which necessarily introduces the anti-C1q antibody or Fab fragment into the circulation for distribution through the blood (a mixture of red blood cells, white blood cells, and platelets) and vascular system (veins, venules, capillaries, arterioles, and arteries), including highly vascularized tissues (e.g. alveoli and glomeruli). Lastly, the wherein clauses of the instant claims that recite that C1q selective inhibition “spares C1q activity outside the subject’s blood space” and “reduces tissue damage in highly vascularized tissues” are intended results of the claimed method that do not impose additional limitations on the either the structure of the claimed anti-C1q Fab nor the administration step. As such, the anti-C1q antibody and method of treatment disclosed by the combined teachings of the prior art are not patentably distinct from the instantly claimed method.
Conclusion
No claims are allowable.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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