DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 03/30/2026 has been entered.
Claim Status
Claims 1-38 have been cancelled and claim 39 has been amended, as requested in the amendment filed on 03/30/2026. Following the amendment, claims 39 and 94-95 are pending in the instant application.
Claims 39 and 94-95 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 39 and 94-95 have an effective filing date of April 6, 2012 corresponding to PRO 61/621,461.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/30/2026 was filed after the mailing date of the Final Office Action on 10/29/2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112 - Withdrawn
Claim 93 was rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. Claim 93 has been cancelled, rendering its rejection moot. Thus, the rejection of claim 93 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn.
Claim Rejections - 35 USC § 103 - Withdrawn
Claims 39 and 93-95 were rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over US 2003/0186419 A1 (previously cited on PTO-892; herein after referred to as "Jensenius") in view of US 2012/0225437 A1 (previously cited on PTO-892; herein after referred to as "Gingras") and non-patent literature by Takahashi et. al. (J. Exp. Med., 2010, 207(1); herein after referred to as "Takahashi") as evidenced by non-patent literature by Barratt and Weitz (Frontiers in Immunology, 2021, 12(712572); herein after referred to as "Barratt").
It is noted that claim 93 has been cancelled, rendering its rejection moot. Furthermore, it is noted that instant claim 1 has been amended to incorporate the subject matter of previous claim 93 wherein instant claim 1 now recites that the MASP-3 inhibitory antibody (or antigen -binding fragment thereof) specifically binds to the serine protease domain of human MASP-3 (corresponding to amino acid residues 450-711 of instant SEQ ID NO: 8).
On Pages 5-8 of Remarks (03/30/2026), Applicant argues the following:
Jensenius is silent about paroxysmal nocturnal hemoglobinuria (PNH) and fails to teach or suggest the use of a MASP-3 inhibitory antibody which inhibits Factor D maturation, thereby inhibiting the alternative pathway, to treat a patient suffering from PNH. Applicant further argues that Jensenius teaches away from the instant claims wherein the assays used to measure MASP-3 activity are carried out under conditions which minimize or eliminate interference from the alternative pathway.
The deficiencies of Jensenius are not remedied by Gingras and Takahashi. Gingras is completely silent to with respect to any MASP antibodies and does not teach or suggest the use of an antibody that specifically binds to MASP-3 for any purpose, wherein Applicant further argues that an inhibitor identified using the screening assay of Gingras would not be specific to MASP-3, but rather would inhibit MBL interaction with both MASP-1 and MASP-3. Takahashi provides no teaching or suggestion to generate a specific inhibitory MASP-3 antibody to bind to the serine protease domain of human MASP-3 and to inhibit Factor D maturation. Further with regard to Takahashi, Applicant argues that although preliminary experiments show that in addition to MASP-1, MASP-3 has an activity to cleave pro-DF, the reference indicates that further investigation will be required to determine whether some other factor affects the activation of pro-Df through cooperation with MASP-1 and MASP-3; thus it is merely speculative that MASP-3 may have an activity to cleave Factor D and it is unpredictable as to whether the administration of a MASP-3 inhibitory antibody would be expected to inhibit Factor D maturation.
With regard to the post-filing Barratt reference, Applicant argues that the cases cited by the Office apply to the context of inherent anticipation, and do not apply to the obviousness analysis, and furthermore obviousness focuses on the knowledge of a person of ordinary skill in the art at the time of filing the invention. Applicant argues that at the time of filing, the properties of the presently claimed method were not known nor expected in light of Jensenius, Gingras, and Takahashi.
Upon consideration of Applicant’s arguments presented above, the rejection of claims 39 and 93-95 were rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable Jensenius, Gingras, and Takahashi as evidenced by Barratt has been withdrawn.
Double Patenting - Withdrawn
Claims 39 and 93-95 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 and 10-30 of U.S. Patent No. 10,639,369 (herein after referred to as "'369") in view of US 2003/0186419 A1 (previously cited on PTO-892; herein after referred to as "Jensenius"), US 2012/0225437 A1 (previously cited on PTO-892; herein after referred to as "Gingras"), and non-patent literature by Takahashi et. al. (J. Exp. Med., 2010, 207(1); herein after referred to as "Takahashi") as evidenced by non-patent literature by Barratt and Weitz (Frontiers in Immunology, 2021, 12(712572); herein after referred to as "Barratt").
Claims 39 and 93-95 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 and 13-18 of U.S. Patent No. 11,027,015 (herein after referred to as "'015") in view of US 2003/0186419 A1 (previously cited on PTO-892; herein after referred to as "Jensenius"), US 2012/0225437 A1 (previously cited on PTO-892; herein after referred to as "Gingras"), and non-patent literature by Takahashi et. al. (J. Exp. Med., 2010, 207(1); herein after referred to as "Takahashi") as evidenced by non-patent literature by Barratt and Weitz (Frontiers in Immunology, 2021, 12(712572); herein after referred to as "Barratt").
Claims 39 and 93-95 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 and 10-16 of U.S. Patent No. 11,883,493 (herein after referred to as "'493") in view of US 2003/0186419 A1 (previously cited on PTO-892; herein after referred to as "Jensenius"), US 2012/0225437 A1 (previously cited on PTO-892; herein after referred to as "Gingras"), and non-patent literature by Takahashi et. al. (J. Exp. Med., 2010, 207(1); herein after referred to as "Takahashi") as evidenced by non-patent literature by Barratt and Weitz (Frontiers in Immunology, 2021, 12(712572); herein after referred to as "Barratt").
Claims 39 and 93-94 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 67, 69-70, and 72-73 of copending Application No. 18/523,203 (herein after referred to as "'203"), as evidenced by non-patent literature by Barratt and Weitz (Frontiers in Immunology, 2021, 12(712572); herein after referred to as "Barratt"). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 95 was rejected on the ground of nonstatutory double patenting as being unpatentable over claims 67, 69-70, and 72-73 of copending Application No. 18/523,203 (herein after referred to as "'203"), as applied to claims 39 and 93-94 above as evidenced by Barratt and Weitz (Frontiers in Immunology, 2021, 12(712572); herein after referred to as "Barratt"), in view of US 2003/0186419 A1 (previously cited on PTO-892; herein after referred to as "Jensenius").
Upon consideration of Applicant’s amendments and the arguments regarding the cited prior art presented above, the above-listed claim rejections under nonstatutory double patenting in view of Jensenius, Gingras, Takahashi, and/or Barratt are withdrawn.
Claim Rejections - 35 USC § 112 - Maintained
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 39 and 94-95 stand as rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The crux of the rejection below is the same as previously presented. The rejection has been updated merely to emphasize portions of the rejection and reflect the amendment of independent claim 39 to incorporate the limitation of previous claim 93.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
The above-recited claims are drawn to/encompass the following:
A method of increasing the survival of red blood cells in a subject suffering from paroxysmal nocturnal hemoglobinuria (PNH), comprising administering to the subject a composition comprising an amount of a MASP-3 inhibitory monoclonal antibody, or antigen binding fragment thereof that specifically binds to the serine protease domain of human MASP-3 (residues 450-711 of SEQ ID NO: 8) and inhibits factor D maturation effective to increase the survival of red blood cells.
Claim 39 is drawn to a genus of MASP-3 inhibitory monoclonal antibodies defined only by their epitope (i.e., SEQ ID NO: 8) and their function (i.e., inhibiting MASP-3/factor D maturation). Example 15 on Pages 167-173 disclose two adequately described MASP-3 inhibitory monoclonal antibodies that bind instant SEQ ID NO: 8 and inhibit factor D maturation, designated by their secondary identifiers as M3J5 and M3M1. However, Applicant is claiming a large and structurally diverse genus of MASP-3 inhibitory monoclonal antibodies, claimed only by their epitope and their function.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. As previously indicated, Applicant has only identified two antibody species within the genus claimed. However, given the large number of species encompassed by the genus claimed as well as the lack of correlation between structure and function, the disclosure of said two adequately described species is not sufficiently representative of the entire claimed genus. Absent a description of the at least minimal structural features correlating with a functional ability to bind SEQ ID NO: 8 and inhibit MASP-3/factor D maturation which are shared by members of a genus of MASP-3 inhibitory monoclonal antibodies commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish CDR amino acid sequences (or combinations thereof) which may be combined such that the resultant antibody comprises six CDRs that confer the ability to bind SEQ ID NO: 8 and inhibit factor D maturation.
Although screening techniques can be used to isolate antibodies that possess the ability to bind/inhibit MASP-3, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the ‘written description’ requirement is broader than to merely explain how to ‘make and use’; the applicant must also convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.”
Applicant’s attention is also directed to the February 2018 USPTO Memorandum, subject: “Clarification of Written Description Guidance for Claims Drawn to Antibodies and Status of 2008 Training Materials,” hereafter referred to the “Memo.”
The Memo reads as follows:
I. Federal Circuit Clarification of the Law of Written Description As It Applies to Antibodies
Recently, the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. These claims are usually handled in Technology Center 1600. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the ‘newly characterized antigen’ test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional. Id. The Amgen decision will be added to the MPEP in due course.
II. Examples in the 2008 Written Description Training Materials Are Outdated
On March 25, 2008, the USPTO issued revision 1 of the Written Description Training Materials. As indicated on the USPTO web site at https://www.uspto.gov/patent/laws-and-regulations/examination-policy/examination-guidance-and-training-materials, these training materials have been archived. Written description training materials containing examples that reflect developments in the law regarding 35 U.S.C. §§ 101 and 112 are being prepared. The archived training materials are outdated and should not be relied upon as reflecting the current state of the law regarding 35 U.S.C. §§ 101 and 112.
In the instant case, claim 1 recites a MASP-3 inhibitory antibody that specifically binds to a portion of human MASP-3 (SEQ ID NO: 8), and said antigen has been adequately described in the art. However, based upon the Memo, it is submitted that adequate description of an antigen to which an antibody binds, such as MASP-3 (the serine protease domain, more specifically), is not sufficient to adequately describe the genus of antibodies specific for said antigen. Furthermore, as indicated above, the USPTO Written Description Training Materials, dated 03/25/2008, have been archived and no longer reflect the current state of the law regarding 35 U.S.C. 112(a).
As such, claim 39 fails to comply with the written description requirement. Claims 93-95 are included in this rejection as they depend from/encompass claim 39.
Claim 94 stands as rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for recombinant, chimeric, and humanized inhibitory MASP-3 monoclonal antibodies, does not reasonably provide enablement for fully human MASP-3 inhibitory monoclonal antibodies. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The crux of the rejection below is the same as previously presented. The rejection has been updated merely to reflect the change in scope of independent claim 39, which has been incorporate the limitation of previous claim 93, from which claim 94 depends.
The Breadth of the Claims
Claim 94 recites the method of claim 39, wherein the antibody or antigen binding fragment may be selected from a group that includes human antibodies. However, it is noted that the antibodies disclosed by the specification that are MASP-3 inhibitory monoclonal antibodies that bind to the serine protease domain of SEQ ID NO: 8 and inhibit factor D maturation are designated as M3J5 and M3M1, which were produced from a modified DT40 cell line, which is a chicken B cell line, and clones of interest underwent affinity maturation and chimeric IgG was generated, which were suitable of in vitro and in vivo applications and could serve as the starting point for humanization (see Example 15 of the specification). As such, the antibodies disclosed by the specification comprise chicken CDRs, and no human CDRs are disclosed. As such, the full scope of claim 93 as pertains to fully human antibodies is not enabled.
The State/Level of Predictability in the Prior Art
The state of the prior art is such that it is well established in the art that the formation of an intact antigen-binding site of antibodies generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope (Paul, Fundamental Immunology, 3rd Edition, 1993, pp. 292-295, under the heading “Fv Structure and Diversity in Three Dimensions”; previously cited on PTO-892). The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (Paul, page 293, first column, lines 3-8 and line 31 to column 2, line 9 and lines 27-30).
Additionally, Bendig M. M. (Methods: A Companion to Methods in Enzymology, 1995; 8:83-93; previously cited on PTO-892) reviews that the general strategy for “humanizing” antibodies involves the substitution of all six CDRs from a rodent antibody that binds an antigen of interest, and that all six CDRs are involved in antigen binding (see entire document, but especially Figures 1-3). It is noted that Bendig used Kabat CDRs in their humanization process (Pg. 86, Column 2, Paragraph, second). Similarly, the skilled artisan recognized a “chimeric” antibody to be an antibody in which both the heavy chain variable region (which comprises the three heavy chain CDRs) and the light chain variable region (which comprises the three light chain CDRs) of a rodent antibody are recombined with constant region sequences from a human antibody of a desired isotype (see entire document, but especially Figures 1-3).
Thus, the state of the art recognized that it would be highly unpredictable that a specific antibody comprising less than all six parental CDRs would have antigen binding function. The minimal structure which the skilled artisan would consider predictive of the function of binding the antigen of a murine or humanized antibody includes six CDRs (three from the heavy chain variable region and three from the light chain variable region) in the context of framework sequences which maintain their correct spatial orientation and have the requisite binding function. One of skill in the art would neither expect nor predict the appropriate functioning of the antibody fragments and mutated antibodies of the instant claims as broadly as claimed.
Moreover, claims not containing elements critical or essential to the practice of the invention, such as antibodies or antibody fragments not having all of the relevant functional complementarity determining regions (CDRs) in the proper site on an appropriate antibody heavy or light chain framework, are not enabled by the disclosure. See In re Mayhew, 527 F.2d 1229, 188 USPQ 356 (CCPA 1976).
Note that an enabling disclosure for the preparation and use of only a few analogs of a product does not enable all possible analogs where the characteristics of the analogs are unpredictable. See Amgen Inc. v. Chugai Pharmaceutical Co. Ltd. (18 USPQ 2d 1027 (CAFC 1991)).
The Level of Direction Provided by the Inventor/Existence of Working Examples
Example 15 of the instant specification discloses antibodies exemplary MASP-3 inhibitory monoclonal antibodies that bind SEQ ID NO: 8 and inhibit factor D maturation designated as M3J5 and M3M1, which were produced from a modified DT40 cell line, which is a chicken B cell line, and clones of interest underwent affinity maturation and chimeric IgG was generated, which were suitable of in vitro and in vivo applications and could serve as the starting point for humanization (see Example 15 of the specification). As such, the antibodies disclosed by the specification comprise chicken CDRs, not human CDRs, and no human CDRs are provided in the instant disclosure.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make/use fully human MASP-3 inhibitory monoclonal antibodies as claimed with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed antibodies are functional, commensurate in scope with the claimed invention.
With regard to above-listen claim rejections regarding written description and scope of enablement, Applicant argues the following on Pages 3-5 of Remarks:
Regarding the written description rejection, Applicant indicates that independent claim 39 has been amended to incorporate the features of previous claim 93 such that, generally, the MASP-3 inhibitory monoclonal antibody specifically binds the serine protease domain of human MASP-3. Applicant argues that detailed methods for the production of additional MASP-3 inhibitory antibodies are provided as well as suitable binding assays and functional assays for determining the inhibition of factor D maturation. Applicant further argues that the structure of human MASP-3 was known in the art at the time of filing and the structure of antibodies was also well known in the art and antibody technology was well-developed and mature.
Regarding the scope of enablement rejection, Applicant argues that the instant specification provides guidance on how to make humanized MASP- inhibitory monoclonal antibodies. Applicant specifically points to Paragraph 0294 of the instant specification, which recites that “humanized or fully human antibodies specific to MASP-1, MASP-2, or MASP-3” can be produced by “one of several methods known to one of ordinary skill in the art” as described in various cited references. Applicant further argues that there are commercial entities that will synthesize humanized antibodies from specific murine antibodies. Thus, Applicant argues that one of ordinary skill in the art would be able to make and use humanized MASP-3 antibodies without undue experimentation.
Applicant’s arguments have been fully considered, but are deemed not persuasive.
With regard to the arguments presented against the written description rejection, it is specifically noted that the adequate description of only two antibodies that are MASP-3 inhibitory monoclonal antibodies that specifically bind the serine protease domain of human MASP-3 and inhibit factor D maturation is not sufficiently representative of the entire claimed genus. To satisfy the written description requirement there must be a sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics. The mere recitation of the antigen/epitope to which a genus of antibodies binds is not sufficient absent the establishment of a structural correlation/relationship shared among all or at least most of the species encompassed by the genus of antibodies sharing that function. Furthermore, the arguments regarding screening techniques to identify antibodies is not pertinent to the written description requirement, which is severable from enablement.
With regard to the arguments presented against the scope of enablement rejection, it is acknowledged that the production of humanized antibodies was identified as being enabled by the instant specification, but the production of human antibodies is not. The only explicit working examples provided by the instant specification are antibodies having non-human CDRs, wherein said antibodies are identified as a starting point for the production of humanized antibodies. However, as is established in the art, the production of functional antibodies requires all parental CDRs and the appropriate heavy/light chain frameworks, which must then associate correctly. Production of fully-human antibodies from non-human CDRs is not enabled by the instant specification.
Claim Rejections - 35 USC § 103 - New
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 39 and 94-95 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over US 2003/0186419 A1 (previously cited on PTO-892; herein after referred to as “Jensenius”) in view of US 2012/0225437 A1 (previously cited on PTO-892; herein after referred to as "Gingras"), non-patent literature by Iwaki et. al. (The Journal of Immunology, 2011, 187, 3751-3758; herein after referred to as “Iwaki”), and non-patent literature by Lindorfer et. al. (Blood, 2010, 115(11), 2283-2291; herein after referred to as “Lindorfer”).
Specifically with regard to independent claim 39, the claim is drawn to a method of “increasing the survival of red blood cells” comprising the active step of administering a composition comprising an amount of, generally, a MASP-3 inhibitory monoclonal antibody that It is noted that increasing the survival of red blood cells is merely an intended result that will necessarily occur when the active step of administering the composition is performed; thus, the limitations of the claim regarding “increasing survival of red blood cells” are not given patentable weight.
Jensenius teaches the isolation and characterization of a lectin associated serine protease (MASP-3), wherein MASP-3 shows some homology with the previously reported MASPs (MASP-1 and MASP-2) and the two C1q-associated serine proteases, C1r and C1s (Paragraph 0009). MBL is structurally related to the C1q subcomponent of component C1 of complement, and it appears that MBL activates the complement system via an associated serine protease termed MASP or p100, which is similar to the C1r and C1s components of the classical pathway; the new complement activation pathway is called the MBLectin pathway (Paragraph 0003). Jensenius purified and characterized MASP-3 and, like MASP-1 and MASP-2, MASP-3 partially copurifies with MBL, and is likely to be involved in mediating the biological effects of the MBL complex (i.e., implicated in MBLectin complement activation) (Paragraph 0010). One aspect of the invention features substantially pure MASP-3 polypeptides and nucleic acids encoding such polypeptides; preferably, the MASP-3 polypeptide retains one or more MASP-3 functions, such as being capable of associating with mannan-binding lectin (MEL) or/and having serine protease activity, a substantially pure mannan-binding lectin associated serine protease-3 (MASP-3) polypeptide, preferably a polypeptide being capable of associating with mannan-binding lectin (MEL), and another aspect of the invention is the production of anti-MASP-3 antibodies and their use (Paragraphs 0011-0012). Some MASP-3 polypeptides of the invention are capable of competitively inhibiting one of the MASP-3 activities (e.g., serine protease activity) and other MASP-3 polypeptides are useful antigens or haptens for producing antibodies (Paragraph 0013). The antibodies of the invention include, for example, monoclonal, polyclonal, and engineered antibodies, which specifically bind MASP-3 wherein by "specifically binds" it is meant an antibody that recognizes and binds to a particular antigen (e.g., a MASP-3 polypeptide of the invention), but which does not substantially recognize or bind to other molecules (Paragraph 0082). The invention also features antagonists and agonists of MASP-3 that can inhibit or enhance one or more of the functions or activities of MASP-3, respectively; suitable antagonists can include small molecules (i.e., molecules with a molecular weight below about 500), large molecules (i.e., molecules with a molecular weight above about 500), antibodies that bind and "neutralize" MASP-3, polypeptides which compete with a native form of MASP-3 for binding to a protein, e.g., MEL, and nucleic acid molecules that interfere with transcription of MASP-3 (for example, antisense nucleic acid molecules and ribozymes) (Paragraph 0083). The invention further encompasses methods for treating disorders associated with aberrant expression or activity of MASP-3; the invention includes methods for treating disorders associated with excessive expression or activity of MASP-3 wherein such methods entail administering a compound which decreases the expression or activity of MASP-3 (Paragraph 0085). Exemplary MASP-3 polypeptides of the invention are disclosed in Paragraph 0140: polypeptides comprising SEQ ID NO: 1 and/or SEQ ID NO: 2, or functional equivalents thereof. Antibodies can be produced by administering a MASP-3 polypeptide or DNA encoding any such peptide to an animal wherein the antibody selectively binds MASP-3 (Paragraph 0160); antibodies may be monoclonal (Paragraph 0161). Antibodies may be used in a method for inhibiting abnormal MASP-3 activity (Paragraph 0168). It is specifically noted that Jensenius SEQ ID NOs: 1 and 2 consist of animo acid sequences comprised within SEQ ID NO: 8. Specifically, Jensenius SEQ ID NOs: 1 and 2 correspond to residues 450-469 and 463-520, respectively, of instant SEQ ID NO: 8 (i.e., they are polypeptide fragments of the serine protease domain of MASP-3). As such, one of ordinary skill in the art, based on the teachings of Jensenius, could screen for/arrive at an inhibitory MASP-3 monoclonal antibody that is specific for the serine protease domain of MASP-3 and is capable of inhibiting MASP-3 activities (i.e., serine protease activity). Thus, Jensenius teaches MASP-3 inhibitory agents, including MASP-3 antibodies specific for the serine protease domain of MASP-3, and the administration of such inhibitors for treating disorders associated with MASP-3.
However, Jensenius does not specifically teach the use of MASP-3 inhibitory monoclonal antibodies in subjects with paroxysmal nocturnal hemoglobinuria (PNH) nor does Jensenius suggest that such antibodies would inhibit factor D maturation and increase the survival of red blood cells. These deficiencies are remedied by Gingras, Iwaki, and Lindorfer.
Gingras teaches methods and compositions to inhibit MASP protein activity using small molecule inhibitors and methods for identifying inhibitors of MASP protein activity (Paragraph 0003). MASP proteins include, e.g., MASP-1 protein, MASP-2 protein, and MASP-3 protein wherein the MASP protein can be a mammalian protein or a human protein and the disease is caused by misregulation of MASP protein activity (Paragraphs 0021-0022). Gingras discloses various diseases that can be treated by administration of a MASP protein inhibitor that is a small molecule, one of which includes PNH (Paragraph 0023). Thus, Gingras teaches using MASP-3 inhibitors to treat conditions such as PNH.
Iwaki teaches that mannose-binding lectin (MBL)-associated serine proteases (MASPs) are responsible for activation of the lectin complement pathway, wherein three types of MASPs (MASP-1, MASP-2, and MASP-3) are complexed with MBL and ficolins in serum; although MASP-1 and MASP-2 are known to contribute to complement activation, the function of MASP-3 remains unclear, and in the study the authors investigated the mechanism of MASP-3 activation and its substrate using the recombinant mouse MASP-3 (rMASP-3) and several
different types of MASP-deficient mice (Abstract). Sera from all MASPs-deficient mice showed significantly lower C3 deposition activity on the bacteria compared with that of wild-type serum,
and addition of rMASP-3 to the deficient serum restored C3 deposition; the low C3 deposition in sera from all MASPs-deficient mice was probably caused by the low level factor B activation that was ameliorated by the addition of rMASP-3 (Id.). Furthermore, rMASP-3 directly activated factors B and D in vitro; these results suggested that MASP-3 complexed with MBL is converted to an active form by incubation with bacterial targets, and that activated MASP-3 triggered the initial activation step of the alternative complement pathway (Id.).
Lindorfer teaches that the clinical hallmark of paroxysmal nocturnal hemoglobinuria (PNH) is chronic intravascular hemolysis that is a consequence of unregulated activation of the alternative pathway of complement (APC) (Abstract). Intravascular hemolysis can be inhibited in patients by treatment with eculizumab, a monoclonal antibody that binds complement C5 thereby preventing formation of the cytolytic membrane attack complex of complement; however, in essentially all patients treated with eculizumab, persistent anemia, reticulocytosis, and biochemical evidence of hemolysis are observed, and in a significant proportion, their PNH erythrocytes become opsonized with complement C3 (Id.). These observations suggest that PNH patients treated with eculizumab are left with clinically significant immune-mediated hemolytic
anemia because the antibody does not block APC activation; with a goal of improving
PNH therapy, the authors characterized the activity of anti-C3b/iC3b monoclonal antibody 3E7 in an in vitro model of APC-mediated hemolysis and showed that 3E7 and its chimeric-deimmunized derivative H17 block both hemolysis and C3 deposition on PNH erythrocytes (Id.). The antibody is specific for the APC C3/C5 convertase because classical pathway–mediated hemolysis is unaffected by 3E7/H17; together these findings suggest an approach to PNH treatment in which both intravascular and extravascular hemolysis can be inhibited while preserving important immune functions of the classical pathway of complement (Id.).
Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time the instant invention was filed to administer to a subject suffering from PNH a composition comprising an amount of a MASP-3 inhibitory monoclonal antibody, or antigen-binding fragment thereof, that specifically binds to the serine protease domain of human MASP-3 and inhibits factor D maturation effective to increase the survival of red blood cells. One of ordinary skill in the art would have been motivated to use MASP-3 inhibitory monoclonal antibodies taught by Jensenius, wherein said antibodies may specifically bind the serine protease domain of human MASP-3, in the treatment of PNH, as suggested by Gingras, because Iwaki teaches that MASPs are responsible for the activation of the alternative complement pathway and, more specifically, MASP-3 triggers the initial activation of the alternative complement pathway and activates factors B and D (i.e., plays a role in factor D maturation) and Lindorfer suggests a therapeutic approach to PNH wherein earlier intervention in the alternative complement pathway (e.g., relative to eculizumab) and/or preventing initial alternative pathway activation while preserving the function of the classical pathway. Such a therapeutic approach to PNH would reasonably be expected to be effective such that the inhibitory monoclonal antibody specific for the serine protease domain of MASP-3 would be expected to inhibit MASP-3 activity (i.e., serine protease activity), as suggested by Jensenius, and would reasonably be expected to subsequently treat PNH, as suggested by Gingras, by way of preventing the initial activation of the alternative complement pathway, as suggested by Iwaki and Lindorfer.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, it is noted that:
(1) Jensenius discloses MASP-3 inhibitory agents, including MASP-3 antibodies specific for the serine protease domain of MASP-3, and the administration of such inhibitors for treating disorders associated with MASP-3.
(2) Gingras discloses the use of MASP inhibitors (i.e., small molecule inhibitors) in the treatment of various disorders, including PNH.
(3) Iwaki discloses that MASP-3 triggers the initial activation of the alternative complement pathway wherein MASP-3 also has a role in the activation/maturation of factors B and D.
(4) Lindorfer suggests therapeutic approaches to PNH wherein the alternative complement pathway is targeted/inhibited at early/initial steps of the pathway (e.g., relative to eculizumab) and suggests that preventing activation of the alternative complement pathway, while keeping the classical complement pathway intact, is a desirable approach to PNH treatment.
Thus, to one of ordinary skill in the art, it would have been obvious to use the inhibitory monoclonal antibodies of Jensenius, which may be specific to the serine protease domain of MASP-3, in a therapeutic approach to treating subjects suffering from PNH because inhibition of MASPs (i.e., MASP-1, MASP-2, and MASP-3) is an established approach to the treatment of various disorders (e.g., PNH) as disclosed by Gingras and the role of MASP-3 in the initial activation of the alternative complement pathway and the activation/maturation of factor D was established by Iwaki and Lindorfer indicates a need for and suggests a therapeutic approach to PNH that targets the early/initial steps of the alternative complement pathway in order to inhibit both intravascular and extravascular hemolysis (i.e., increase red blood cell survival).
With regard to claim 94, Jensenius indicates that references to constructs of antibodies (or fragments thereof coupled to a compound comprising a detectable marker) includes constructs made by any technique, including chemical means or by recombinant techniques (Paragraph 0082). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 95, Jensenius further teaches that inhibitors of the biological activity of MASP-3 may be employed to control the complement activating activity and inflammatory activity of MASP-3 or for neutralizing the inhibitory effect of MASP-3 thus giving an overall increase of the activity of the MEL/MASP complex (Paragraph 0244) wherein MASP-3 activity may be inhibited by a compound capable of inhibiting the complex formation of MEL and MASP-3 and the compound may comprise an antibody capable of binding MASP-3 thereby inhibiting MASP-3 activity (Paragraphs 0245-0246). Pharmaceutical compositions according to the invention may comprise one or more polypeptides or compounds (e.g., antibodies) of the invention, and according to methods of the invention the compositions can be administered by injection by gradual infusion over time or by any other medically acceptable mode; administration may, for example, be intravenous, intraperitoneal, intramuscular, intracavity, subcutaneous or transdermal (i.e., systemic) (Paragraph 0253). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
Response to Arguments
Applicant’s arguments, which are fully presented above, filed 03/30/2026, with respect to the rejection of claims 39 and 93-95 under 35 USC 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new grounds of rejection is made in view of US 2003/0186419 A1 (previously cited on PTO-892; herein after referred to as “Jensenius”) in view of US 2012/0225437 A1 (previously cited on PTO-892; herein after referred to as "Gingras"), non-patent literature by Iwaki et. al. (The Journal of Immunology, 2011, 187, 3751-3758; herein after referred to as “Iwaki”), and non-patent literature by Lindorfer et. al. (Blood, 2010, 115(11), 2283-2291; herein after referred to as “Lindorfer”). Since the new grounds of rejection rely on the previously cited Jensenius and Gingras references, the arguments regarding these references are addressed below.
The pertinent arguments are as follows:
Jensenius is silent about paroxysmal nocturnal hemoglobinuria (PNH) and fails to teach or suggest the use of a MASP-3 inhibitory antibody which inhibits Factor D maturation, thereby inhibiting the alternative pathway, to treat a patient suffering from PNH. Applicant further argues that Jensenius teaches away from the instant claims wherein the assays used to measure MASP-3 activity are carried out under conditions which minimize or eliminate interference from the alternative pathway.
The deficiencies of Jensenius are not remedied by Gingras. Gingras is completely silent to with respect to any MASP antibodies and does not teach or suggest the use of an antibody that specifically binds to MASP-3 for any purpose, wherein Applicant further argues that an inhibitor identified using the screening assay of Gingras would not be specific to MASP-3, but rather would inhibit MBL interaction with both MASP-1 and MASP-3.
With regard to the arguments pertaining to the Jensenius reference, it is acknowledged that the reference is (i) silent to the treatment of PNH specifically, and does not (ii) explicitly suggest that inhibitory antibodies specific to the serine protease domain of MASP-3 would inhibit factor D maturation. However, these deficiencies are remedied (i) by the combination of Gingras, Iwaki, and Lindorfer and (ii) by Iwaki, respectively, as is detailed in the new grounds of rejection above. With regard to the argument of teaching away, it is specifically noted that preferred embodiments are not the only teaching of a reference. “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)).
PNG
media_image1.png
18
19
media_image1.png
Greyscale
A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). See also > Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005)(reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component); < Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir. 1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. “The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed.”). Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). “A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use.” In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994). Furthermore, “[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). The conditions under which MASP-3 activity are evaluated does not negate the fact that MASP-3 activity can be evaluated and the inhibitory effects of the antibodies of Jensenius may be evaluated. Notably, Jensenius discloses assessing activity of MASP-3, which pertains to functional assessment comprising assaying the enzymatic (i.e., serine protease) activity of the compound (Paragraph 0090); inhibitors targeted to the serine protease domain would be expected to inhibit serine protease activity. The context/conditions in which such activity is evaluated would be within the purview of one having ordinary skill in the art.
With regard to the arguments pertaining to Gingras reference, it is noted that the Gingras reference is now merely relied upon for the teaching that MASP inhibitors, including MASP-3 inhibitors, are a therapeutic approach to the treatment of diseases including PNH. The newly cited Iwaki and Lindorfer references further motivate applying the antibodies of Jensenius for the treatment of PNH wherein Iwaki teaches the function of activated MASP-3 (activation of the alternative complement pathway and factor B and D activation/maturation) and Lindorfer indicates early intervention in the alternative complement pathway, including preventing pathway activation, is a desirable therapeutic approach to PNH which is clinically characterized by unregulated alternative complement pathway activation.
Furthermore, it is noted that it has been held that one cannot show non-obviousness by attacking references individually where, as here, the rejections are based on combinations of references. In re Keller, 208 USPQ 871 (CCPA 1981). Moreover, there is no requirement that an “express, written motivation to combine must appear in prior art references before a finding of obviousness.” See Ruiz v. A.B. Chance Co., 357 F.3d 1270, 1276, 69 USPQ2d 1686, 1690 (Fed. Cir. 2004). As recited in MPEP 2144(I), the rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992); see also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); Ex parte Clapp, 227 USPQ 972 (Bd. Pat. App. & Inter. 1985) (examiner must present convincing line of reasoning supporting rejection); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning).
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 39 and 94-95 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 6-8, and 30 of U.S. Patent No. 10,6239,369 (herein after referred to as “’369”) in view of US 2003/0186419 A1 (previously cited on PTO-892; herein after referred to as “Jensenius”) in view of US 2012/0225437 A1 (previously cited on PTO-892; herein after referred to as "Gingras"), non-patent literature by Iwaki et. al. (The Journal of Immunology, 2011, 187, 3751-3758; herein after referred to as “Iwaki”), and non-patent literature by Lindorfer et. al. (Blood, 2010, 115(11), 2283-2291; herein after referred to as “Lindorfer”).
Claims 39 and 94-95 are rendered obvious by the combined teachings of the prior art above as discussed in the 103 section, the 103 being incorporated here. The addition of the patented claims over related subject matter only further supports this obviousness.
Claim 1 of ‘369 is drawn to an isolated antibody, or antigen-binding fragment thereof, that binds to MASP-3 comprising a heavy chain variable region and a light chain variable region comprising the recited sequences. Claim 3 further limits claim 1 wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody, and a murine antibody. Claim 6 further limits claim 3 wherein the antibody or antigen-binding fragment thereof is humanized. Claims 7-8 further limit claim 1 wherein, respectively: (i) the antibody binds to the serine protease domain of human MASP-3 with an affinity of less than 500 pM and/or (ii) the antibody inhibits alternative pathway activation in mammalian blood. Claim 30 is drawn to a composition comprising the antibody or antigen-binding fragment of any of claims 1 or 6 and a pharmaceutically acceptable excipient.
However, it is noted that ‘369 does not explicitly claim that the isolated antibody is capable of inhibiting factor D maturation and increasing red blood cell survival in patients suffering from PNH. These deficiencies are addressed by the cited references, as provided by the teachings specified in the 103 section.
Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time the instant invention was filed to administer to a subject suffering from PNH a composition comprising an amount of a MASP-3 inhibitory monoclonal antibody, or antigen-binding fragment thereof, that specifically binds to the serine protease domain of human MASP-3 and inhibits factor D maturation effective to increase the survival of red blood cells. One of ordinary skill in the art would have been motivated to use MASP-3 inhibitory monoclonal antibodies, such as those claimed by ‘369 and as taught by Jensenius, further wherein said antibodies may specifically bind the serine protease domain of human MASP-3, in the treatment of PNH, as suggested by Gingras, because Iwaki teaches that MASPs are responsible for the activation of the alternative complement pathway and, more specifically, MASP-3 triggers the initial activation of the alternative complement pathway and activates factors B and D (i.e., plays a role in factor D maturation) and Lindorfer suggests a therapeutic approach to PNH wherein earlier intervention in the alternative complement pathway (e.g., relative to eculizumab) and/or preventing initial alternative pathway activation while preserving the function of the classical pathway. Such a therapeutic approach to PNH would reasonably be expected to be effective such that the inhibitory monoclonal antibody specific for the serine protease domain of MASP-3 would be expected to inhibit MASP-3 activity (i.e., serine protease activity), as suggested by Jensenius, and would reasonably be expected to subsequently treat PNH, as suggested by Gingras, by way of preventing the initial activation of the alternative complement pathway, as suggested by Iwaki and Lindorfer.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, it is noted that:
(1) ‘369 discloses MASP-3 specific antibodies, which specifically bind the serine protease domain of human MASP-3, and Jensenius discloses MASP-3 inhibitory agents, including MASP-3 antibodies specific for the serine protease domain of MASP-3, and the administration of such inhibitors for treating disorders associated with MASP-3.
(2) Gingras discloses the use of MASP inhibitors (i.e., small molecule inhibitors) in the treatment of various disorders, including PNH.
(3) Iwaki discloses that MASP-3 triggers the initial activation of the alternative complement pathway wherein MASP-3 also has a role in the activation/maturation of factors B and D.
(4) Lindorfer suggests therapeutic approaches to PNH wherein the alternative complement pathway is targeted/inhibited at early/initial steps of the pathway (e.g., relative to eculizumab) and suggests that preventing activation of the alternative complement pathway, while keeping the classical complement pathway intact, is a desirable approach to PNH treatment.
Thus, to one of ordinary skill in the art, it would have been obvious to use the inhibitory monoclonal antibodies of ‘369 and/or Jensenius, which may be specific to the serine protease domain of MASP-3, in a therapeutic approach to treating subjects suffering from PNH because inhibition of MASPs (i.e., MASP-1, MASP-2, and MASP-3) is an established approach to the treatment of various disorders (e.g., PNH) as disclosed by Gingras and the role of MASP-3 in the initial activation of the alternative complement pathway and the activation/maturation of factor D was established by Iwaki and Lindorfer indicates a need for and suggests a therapeutic approach to PNH that targets the early/initial steps of the alternative complement pathway in order to inhibit both intravascular and extravascular hemolysis (i.e., increase red blood cell survival).
Claims 39 and 94-95 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9, 11-13, and 18-19 of U.S. Patent No. 11,027,015 (herein after referred to as “’015”) in view of US 2003/0186419 A1 (previously cited on PTO-892; herein after referred to as “Jensenius”) in view of US 2012/0225437 A1 (previously cited on PTO-892; herein after referred to as "Gingras"), non-patent literature by Iwaki et. al. (The Journal of Immunology, 2011, 187, 3751-3758; herein after referred to as “Iwaki”), and non-patent literature by Lindorfer et. al. (Blood, 2010, 115(11), 2283-2291; herein after referred to as “Lindorfer”).
Claims 39 and 94-95 are rendered obvious by the combined teachings of the prior art above as discussed in the 103 section, the 103 being incorporated here. The addition of the patented claims over related subject matter only further supports this obviousness.
Claims 1 and 13 of ‘015 are each drawn to an isolated antibody, or antigen-binding fragment thereof, that binds to MASP-3 comprising a heavy chain variable region and a light chain variable region comprising the recited sequences. Claim 9 further limits claim 1 wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody, and a murine antibody. Claims 11 and 18 further limit claims 1 and 13, respectively, wherein the antibody inhibits alternative pathway activation in mammalian blood. Claims 12 and 13 are drawn to compositions comprising the antibody or antigen-binding fragment of claims 1 and 13, respectively, and a pharmaceutically acceptable excipient. Furthermore, it is noted that the disclosure of ‘015 indicates that an inherent feature of the claimed antibodies is that they specifically bind the serine protease domain of human MASP-3 (see Column 7, Lines 14-57).
However, it is noted that ‘015 does not explicitly claim that the isolated antibody is capable of inhibiting factor D maturation or increasing red blood cell survival in patients suffering from PNH. These deficiencies are addressed by the cited references, as provided by the teachings specified in the 103 section.
Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time the instant invention was filed to administer to a subject suffering from PNH a composition comprising an amount of a MASP-3 inhibitory monoclonal antibody, or antigen-binding fragment thereof, that specifically binds to the serine protease domain of human MASP-3 and inhibits factor D maturation effective to increase the survival of red blood cells. One of ordinary skill in the art would have been motivated to use MASP-3 inhibitory monoclonal antibodies, such as those claimed by ‘015 and as taught by Jensenius, further wherein said antibodies may specifically bind the serine protease domain of human MASP-3, in the treatment of PNH, as suggested by Gingras, because Iwaki teaches that MASPs are responsible for the activation of the alternative complement pathway and, more specifically, MASP-3 triggers the initial activation of the alternative complement pathway and activates factors B and D (i.e., plays a role in factor D maturation) and Lindorfer suggests a therapeutic approach to PNH wherein earlier intervention in the alternative complement pathway (e.g., relative to eculizumab) and/or preventing initial alternative pathway activation while preserving the function of the classical pathway. Such a therapeutic approach to PNH would reasonably be expected to be effective such that the inhibitory monoclonal antibody specific for the serine protease domain of MASP-3 would be expected to inhibit MASP-3 activity (i.e., serine protease activity), as suggested by Jensenius, and would reasonably be expected to subsequently treat PNH, as suggested by Gingras, by way of preventing the initial activation of the alternative complement pathway, as suggested by Iwaki and Lindorfer.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, it is noted that:
(1) ‘015 discloses MASP-3 specific antibodies, which specifically bind the serine protease domain of human MASP-3, and Jensenius discloses MASP-3 inhibitory agents, including MASP-3 antibodies specific for the serine protease domain of MASP-3, and the administration of such inhibitors for treating disorders associated with MASP-3.
(2) Gingras discloses the use of MASP inhibitors (i.e., small molecule inhibitors) in the treatment of various disorders, including PNH.
(3) Iwaki discloses that MASP-3 triggers the initial activation of the alternative complement pathway wherein MASP-3 also has a role in the activation/maturation of factors B and D.
(4) Lindorfer suggests therapeutic approaches to PNH wherein the alternative complement pathway is targeted/inhibited at early/initial steps of the pathway (e.g., relative to eculizumab) and suggests that preventing activation of the alternative complement pathway, while keeping the classical complement pathway intact, is a desirable approach to PNH treatment.
Thus, to one of ordinary skill in the art, it would have been obvious to use the inhibitory monoclonal antibodies of ‘015 and/or Jensenius, which may be specific to the serine protease domain of MASP-3, in a therapeutic approach to treating subjects suffering from PNH because inhibition of MASPs (i.e., MASP-1, MASP-2, and MASP-3) is an established approach to the treatment of various disorders (e.g., PNH) as disclosed by Gingras and the role of MASP-3 in the initial activation of the alternative complement pathway and the activation/maturation of factor D was established by Iwaki and Lindorfer indicates a need for and suggests a therapeutic approach to PNH that targets the early/initial steps of the alternative complement pathway in order to inhibit both intravascular and extravascular hemolysis (i.e., increase red blood cell survival).
Claims 39 and 94-95 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5-7, and 10 of U.S. Patent No. 11,883,493 (herein after referred to as “’493”) in view of US 2003/0186419 A1 (previously cited on PTO-892; herein after referred to as “Jensenius”) in view of US 2012/0225437 A1 (previously cited on PTO-892; herein after referred to as "Gingras"), non-patent literature by Iwaki et. al. (The Journal of Immunology, 2011, 187, 3751-3758; herein after referred to as “Iwaki”), and non-patent literature by Lindorfer et. al. (Blood, 2010, 115(11), 2283-2291; herein after referred to as “Lindorfer”).
Claim 1 of ‘493 is drawn to an isolated antibody, or antigen-binding fragment thereof, that binds to MASP-3 comprising a heavy chain variable region and a light chain variable region comprising the recited sequences. Claim 2 further limits claim 1 wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody, and a murine antibody. Claim 5 further limits claim 1 wherein the antibody or antigen-binding fragment thereof is humanized. Claims 6-7 further limit claim 1 wherein, respectively: (i) the antibody binds to the serine protease domain of human MASP-3 with an affinity of less than 500 pM and/or (ii) the antibody inhibits alternative pathway activation in mammalian blood. Claim 10 is drawn to a composition comprising the antibody or antigen-binding fragment of any of claims 1 or 6 and a pharmaceutically acceptable excipient.
However, it is noted that ‘493 does not explicitly claim that the isolated antibody is capable of inhibiting factor D maturation or increasing red blood cell survival in patients suffering from PNH. These deficiencies are addressed by the cited references, as provided by the teachings specified in the 103 section.
Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time the instant invention was filed to administer to a subject suffering from PNH a composition comprising an amount of a MASP-3 inhibitory monoclonal antibody, or antigen-binding fragment thereof, that specifically binds to the serine protease domain of human MASP-3 and inhibits factor D maturation effective to increase the survival of red blood cells. One of ordinary skill in the art would have been motivated to use MASP-3 inhibitory monoclonal antibodies, such as those claimed by ‘493 and as taught by Jensenius, further wherein said antibodies may specifically bind the serine protease domain of human MASP-3, in the treatment of PNH, as suggested by Gingras, because Iwaki teaches that MASPs are responsible for the activation of the alternative complement pathway and, more specifically, MASP-3 triggers the initial activation of the alternative complement pathway and activates factors B and D (i.e., plays a role in factor D maturation) and Lindorfer suggests a therapeutic approach to PNH wherein earlier intervention in the alternative complement pathway (e.g., relative to eculizumab) and/or preventing initial alternative pathway activation while preserving the function of the classical pathway. Such a therapeutic approach to PNH would reasonably be expected to be effective such that the inhibitory monoclonal antibody specific for the serine protease domain of MASP-3 would be expected to inhibit MASP-3 activity (i.e., serine protease activity), as suggested by Jensenius, and would reasonably be expected to subsequently treat PNH, as suggested by Gingras, by way of preventing the initial activation of the alternative complement pathway, as suggested by Iwaki and Lindorfer.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, it is noted that:
(1) ‘493 discloses MASP-3 specific antibodies, which specifically bind the serine protease domain of human MASP-3, and Jensenius discloses MASP-3 inhibitory agents, including MASP-3 antibodies specific for the serine protease domain of MASP-3, and the administration of such inhibitors for treating disorders associated with MASP-3.
(2) Gingras discloses the use of MASP inhibitors (i.e., small molecule inhibitors) in the treatment of various disorders, including PNH.
(3) Iwaki discloses that MASP-3 triggers the initial activation of the alternative complement pathway wherein MASP-3 also has a role in the activation/maturation of factors B and D.
(4) Lindorfer suggests therapeutic approaches to PNH wherein the alternative complement pathway is targeted/inhibited at early/initial steps of the pathway (e.g., relative to eculizumab) and suggests that preventing activation of the alternative complement pathway, while keeping the classical complement pathway intact, is a desirable approach to PNH treatment.
Thus, to one of ordinary skill in the art, it would have been obvious to use the inhibitory monoclonal antibodies of ‘493 and/or Jensenius, which may be specific to the serine protease domain of MASP-3, in a therapeutic approach to treating subjects suffering from PNH because inhibition of MASPs (i.e., MASP-1, MASP-2, and MASP-3) is an established approach to the treatment of various disorders (e.g., PNH) as disclosed by Gingras and the role of MASP-3 in the initial activation of the alternative complement pathway and the activation/maturation of factor D was established by Iwaki and Lindorfer indicates a need for and suggests a therapeutic approach to PNH that targets the early/initial steps of the alternative complement pathway in order to inhibit both intravascular and extravascular hemolysis (i.e., increase red blood cell survival).
Claims 39 and 94-95 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 67, 69-70, and 72-73 of copending Application No. 18/523,203 (herein after referred to as “’203”). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 67 of ‘203 is drawn to a method of inhibiting the alternative pathway complement activation in a mammal comprising administering a high affinity MASP-3 inhibitory antibody or antigen-binding fragment thereof sufficient to inhibit alternative pathway complement activation wherein said antibody or antigen-binding fragment comprises the recited sequences. Claims 69-70 further limit claim 67 wherein (i) the antibody binds the serine protease domain of MASP-3 and (ii) inhibits factor D maturation, respectively. Claims 72-73 further limit the method of claim 67 wherein, respectively, (i) the antibody selectively inhibits the alternative pathway without affecting classical pathway activation and (ii) the subject in need of the method of claim 1 can include a subject suffering from, for example, PNH. From the specification of ‘203, it is noted that the claimed antibodies are monoclonal, mouse-human chimeric antibodies isolated from hybridomas and comprising mouse variable regions and human IgG4 heavy chains and kappa light chains (see Example 15, Pages 239-260). As such, the claims of ‘203 are drawn to administering inhibitory monoclonal, mouse-human chimeric inhibitory MASP-3 antibodies, which specifically bind the serine protease domain of MASP-3 and inhibit factor D maturation to selectively inhibit alternative pathway complement activation, in a subject that is suffering from, for example, PNH; the active steps of the instant claims are claimed by ‘203, and as such the intended result of increasing the survival of red blood cells would necessarily occur. As such, claims 67, 69-70, and 72-73 read directly on instant claims 39 and 94-95.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 39 and 94-95 are pending. Claims 39 and 94-95 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA RAE STONEBRAKER whose telephone number is (571)270-0863. The examiner can normally be reached Monday-Thursday 7:00 am - 5:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
Prosecution Insights