DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s election without traverse of Group I (drawn to an antibody) and the species of PAD2 and PAD4, and the PAD2 binding CDRs recited in claim 66, and PAD4 binding CDRs recited in claim 73 in the Response filed on August 13, 2026 is acknowledged.
Claims 3-10, 13-18, 20-22, 24-28, 30-35, 37-40, 42-49, 51-65, 67-72, 74-79, 81-85, 87-96, 99, 105-107, and 109-112 have been canceled.
Claims 1, 2, 11, 12, 19, 23, 29, 36, 41, 50, 66, 73, 80, 86, 97, 98, 100-104, and 108 are pending.
Claims 98, 100, 101, 104, and 108 have been withdrawn under 37 CFR 1.142(b) as being drawn to nonelected invention.
Claims 1, 2, 11, 12, 19, 23, 29, 36, 41, 50, 66, 73, 80, 86, 97, 102, and 103 are pending and currently under consideration.
3. 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.
4. Claims 1, 2, 11, 12, 19, 23, 29, 36, 41, 50, 80, 86, 97, 102, and 103 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 written description requirement. The claims contain 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 claims are drawn to an antibody comprising a peptidyl arginine deiminase 2 (PAD2) binding domain that specifically binds to PAD2 and/or PAD4 binding domain that specifically binds PAD4. Dependent claims, e.g. claim 2, recite the function of the antibody including inhibiting PAD activity in the synovial fluid and/or inhibiting PAD2 and/or PAD4 in immune cells. Dependent claims, e.g. claim 36, further recite that the antibody is a bivalent bispecific antibody comprising Fab that binds PAD2 and Fab that binds PAD4.
The specification discloses specific anti-PAD2 antibodies and anti-PAD4 antibodies with specific amino acid sequences for the six CDRs (e.g. see pages 5-36 of the specification as-filed).
There is insufficient written description in the specification as-filed of the antibody comprising a PAD2 binding domain and /or PAD4 binding domain as recited in the instant claims.
The claims recite a genus of antibody that specifically binds to PAD2 and/or PAD4 as part of the invention without providing a physical structure or testable functional activity for the antibody. The genus of the antibody that binds to PAD2 and/or PAD4 are therefore extremely large. Applicant has disclosed antibodies with specific structures--- amino acid sequences for the six CDRs. Thus, applicant has disclosed only a limited species of the antibodies, namely the antibodies have specific amino acid sequences. The claimed antibody lack a common structure essential for their functions of PAD2 and/or PAD4 binding and the claims do not require any particular structure basis or testable functions be shared by the instant antibodies.
It should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. 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 parent immunoglobulin (Janeway Jr et al., Immunology, 3rd Edition, 1997 Garland Publishing Inc., pages 3:1-3:11.see entire selection). Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), the following is noted. To show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358). Further, an adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361). Indeed, the courts have long ruled that “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.” See Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005). Also, “A sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus.” See AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69.
Artisans are well aware that knowledge of a given antigen (for instance human CD40) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. (J. Mol. Biol., 2003, 334:103-118) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well, see entire document). Similarly, Lloyd et al. (Protein Engineering Design & Selection 2009, 22;3:159-168) teach that a large majority of VH/VL germline gene segments are used in the antibody response to an antigen, even when the antibodies were selected by antigen binding, as their sequencing studies revealed that out of 841 unselected and 5,044 selected antibodies, all but one of the 49 functional VH gene segments was observed (see entire document). Goel et al. (The Journal of Immunology, 2004, 173:7358-7367) disclose the synthesis of three mAbs that bind to the same short (12-mer) peptide and found that the sequences of these antibodies which bound the same epitope exhibited diverse V gene usage indicating their independent germline origin (see entire document). As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data such as that of Edwards et al. indicating the diversity of sequence bound in a population of antibodies that bind to a given antigen no number of species appears to reasonably representative of the breadth of the genus of antibodies that bind the given antigen. Indeed, Kanyavuz et al. (Nature Review Immunology, 2019, 19: 355-368) teach that “Theoretically, under physiological conditions, the human immune system can generate BCRs with 1026 distinct sequences, an astronomical number that is far greater than the calculated number of all B cell clones that can be generated during the lifespan of a healthy human (estimated to be 4 × 1014).
As has already been pointed out, none of the instant claims recite any structure of the antibody to provide the functions of antigen binding or inhibiting PAD-mediated citrullination of proteins, inhibiting PAD activity in synovial fluid, or inhibiting PAD2 and/or PAD4 in immune cells. Thus, all present claims utilize only functional language to describe the antibody.
The specification discloses specific anti-PAD2 antibodies and anti-PAD4 antibodies with specific amino acid sequences for the six CDRs. Such disclosure does not serve to provide a written description of the genus of the antibody as recited as it does not identify any specific structural feature or combination of features which give rise to the functions of antigen binding and the inhibition functions as recited in instant claims.
The species of antibodies disclosed in the specification is not reasonably representative of the species of all possible antibodies defined by binding to PAD2 and/or PAD4 because of the structural diversity found in antibodies that bind the same antigen as discussed by for example Edwards et al., Llyod et al., and Goel et al. discussed above.
Further, as has been discussed above, identifying an antibody simply on the basis of what it binds rather than by identifying the sequence/structure of the antibody in question is generally insufficient to provide sufficient written description of the antibody in question.
Therefore, in view of the breadth of the claims, artisans would reasonably conclude that applicant was not in possession of the full breadth of the antibodies that binds PAD2 and/or PAD4 at the time the instant application was filed.
5. 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.
6. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
7. Claims 1, 2, 11, 19, 23, 80, 97, and 102 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Nielsen et al. (WO 2014/086365, reference on IDS).
Nielsen et al. teach an anti-human PAD2 antibody that inhibits PAD2 activity including extracellular citrullination mediated by PAD2 (e.g. see pages 20-21). Nielsen et al. further teach that the anti-PAD2 antibody does not bind any one of PAD1, PAD3 or PAD4 (e.g. see lines 20-25 in page 21). Nielsen et al. further teach that the antibody can be scFv (e.g. see lines 15-25 in page 8).
Nielsen et al. teach that the human PAD2 protein is highly conserved amongst species between human, rabbit and mouse (e.g. see lines 5-11 in page 11). Thus, the anti-PAD2 antibody would be expected to also bind mouse PAD2. The anti-PAD2 antibody is IgG antibody which comprises an Fc domain (e.g. see lines 15-25 in page 24). Nielsen et al. teach a pharmaceutical composition comprising the anti-NAD2 antibody and a pharmaceutical acceptable carrier (e.g. see paragraph spanning pages 37-38). Nielsen et al. teach that the anti-PAD2 antibodies can be used for treatment of autoimmune diseases (e.g. see lines 5-15 in page 1).
Therefore, the reference teachings anticipate the instant invention.
8. Claims 1, 2, 12, 19, 23, 80, 97, 102, and 103 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sato et al. (US 2018/0044434).
Sato et al. teach an anti-human PAD4 antibody that inhibits citrullination activity mediated by PD4 (e.g. see Abstract). Sato et al. teach that the antibody can be a full length antibody comprising a Fab and Fc region (e.g. see [0069]). Sato et al. teach that the anti-PAD4 antibody binds human PAD4 and mouse PAD4 (e.g. see Example 2 in page 12). Sato et al. further teach a pharmaceutical composition comprising the antibody (e.g. see [0122]).
Sato et la. also teach a kit comprising the anti-PAD4 antibody (e.g. see [0118]). Sato et al. further teach that the antibody can be scFv (e.g. see [0076]).
Furthermore, Sato et al. teach that the anti-PAD4 antibodies were generated by immunizing chickens with modified peptide antigen corresponding to positions 340 to 356 of PAD4 (e.g. see [0133]). As shown below, position 348 of PAD4(M) and PAD3(I) are different:
PAD4 EENMDDQWMQDEMEIGY 17 (340-356)
EN +D+W+QDEME+GY
PAD3 AENRNDRWIQDEMELGY 17 (340-356)
Moreover, Sato et al. teach methods of treating rheumatoid arthritis by administering the anti-PAD4 antibody (e.g. see claims 22).
As such, the prior art anti-PAD4 antibody binding epitope at position 348 would not bind PAD3 without evidence to the contrary.
Therefore, the reference teachings anticipate the instant invention.
9. 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.
10. Claims 1, 23, 29, 36, 41, and 56 are rejected under 35 U.S.C. 103 as being unpatentable over Nielsen et al. (WO 2014/086365, reference on IDS) and Sato et al. (US 2018/0044434) in view of Hansen et al. (US 2005/0100543).
The teachings of Nielsen et al. and Sato et al. have been discussed, supra.
The reference teachings differ from the instant invention by not describing a bispecific IgG anti-PAD2/PAD4 antibody comprising first and second Fabs and an Fc domain and first and second scFvs linked to the carboxy terminal of the Fc, wherein the Fabs or the scFv binds PAD2 or PAD4.
Nielsen et al. further teach that PAD2 and PAD4 are both known to be involved in rheumatoid arthritis and are both present in the inflamed joint in rheumatoid arthritis (e.g. see liens 28-35). It was also known that anti-PAD2 antibody and anti-PAD4 antibody are therapeutic for treating autoimmune diseases as taught by Nielsen et al. and Sato et al. (see discussions above).
Hansen et al. teach bispecific antibodies having desired attributes such as increased affinity, high stability for in vitro and in vivo uses for therapy and in vitro applications (e.g. see [0002]). Hansen et al. teach that the bispecific antibody is shown in FIG. 1 (copied below for convenience). The structure of the bispecific antibody is an IgG with two Fabs at connected to the N-terminus of the Fc and two scFvs at the C-terminal of the Fc.
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It would thus be obvious to one of ordinary skill in the art at the time the instant invention was filed to produce bispecific anti-PAD2/PAD4 antibody using the well known bispecific antibody formular disclosed in Hansen et al. An ordinary skill in the art would have been motivated to do so and have a reasonable expectation of success since both specific anti-PAD2 antibodies and specific anti-PAD4 antibodies including IgG antibody or scFv are available and known to be therapeutic to rheumatoid arthritis (both PAD2 and PAD4 are present in the inflamed joint in rheumatoid arthritis). Hansen et al. teach the bispecific antibodies having desired attributes such as increased affinity, high stability for in vitro and in vivo uses for therapy and in vitro applications. As such, incorporating the known monospecific anti-PAD2 antibody and anti-PAD4 antibody into the bispecific antibody format disclosed by Hansen et al. would provide a bispecific IgG anti-PAD2/PAD4 antibody that can target both PAD2 and PAD4 in inflamed joint in rheumatoid arthritis for treatment. Given that there are only two ways to connect the antigen binding regions, namely either N-terminus or the C-terminus, an ordinary skill in the art would be able to add scFv of anti-PAD2 antibody to the C-terminal of the anti-PAD4 IgG antibody or add scFv anti-PAD4 antibody to the C-terminus of the anti-PAD2 antibody with a reasonable expectation of success.
11. Claims 66 and 73 are objected to as being dependent upon a rejected base claim 1, but would be allowable if rewritten in the independent form including all of the limitations of the base claim and any intervening claims.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHUN DAHLE whose telephone number is (571)272-8142. The examiner can normally be reached Mon-Fri 6:30am-4:00pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHUN W DAHLE/Primary Examiner, Art Unit 1641
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