Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-5, 7, 14-15, 17, 19, 21, 23-25, 27-28, 31, 37 and 41 are pending.
Applicant’s election without traverse of Group I in the reply filed on June 12, 2026 is acknowledged.
Claims 14-15, 17, 23-25, 28, 31, 37 and 41 are withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.
Claims 1-5, 7, 19, 21 and 27, drawn to an antigen-binding fragment there specifically binds FcγRIIA and a pharmaceutical composition comprising said antigen-binding fragment thereof, are being acted upon in this Office Action.
Priority
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on January 29, 2024 has been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
Drawings
The drawings filed on March 30, 2023 are objected to because Figure 6B is cut off. Corrected drawing sheets in compliance with 37 CFR 1.121 (d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as "amended." If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either "Replacement Sheet" or "New Sheet" pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/patents-application- process/filing-online/legal-framework-efs-web), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency –
Claim 4 is objected to under 37 CFR 1.821 through 1.825 for failure to supply a sequence identifier to all disclosed sequences. In particular, the sequences WAWX1WX2TETX3V lack a sequence identifier, see MPEP §2422.01. The particular sequence is not present in the paper copy and computer readable copy of sequence listing. Hence, the disclosure fails to comply with the requirements of 37 CFR 1.821 through 1.825.
Required response – Applicant must provide:
Amendment to claim 4 by inserting the requires SE ID NO,
A substitute computer readable form (CFR) copy of the sequence listing, a substitute paper copy of the sequence listing, as well as any amendment directing its entry into the specification, and a statement that the content of the paper and computer readable copies are the same, and where applicable, include no new matter, as required by 37 CFR 1.82(e-f) or 1.825(b) or 1.825(d).
Specification
The disclosure is objected to under 37 CFR 1.821 through 1.825 for failure to supply a sequence identifier to all disclosed sequences. In particular, the sequences GGGGWAWVWLTETAVGGGGS, and WAWVWLTETAVA on p. 34, the primer sequences ggccagtggatagtcagatgggggtgtcgttttggc, gaggtgaagctggtggagtc, ggatacagttggtgcagcatc, and gatattgtgatgacgcaggct on p. 35 lack a sequence identifier, see MPEP §2422.01. Amending the specification by inserting SEQ ID NO, e.g., GGGGWAWVWLTETAVGGGGS (SEQ ID NO: 10) and WAWVWLTETAVA (SEQ ID NO: 11), ggccagtggatagtcagatgggggtgtcgttttggc (SEQ ID NO: 21), gaggtgaagctggtggagtc (SEQ ID NO: 22), ggatacagttggtgcagcatc (SEQ ID NO: 23), gatattgtgatgacgcaggct (SEQ ID NO: 24) would obviate this issue.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claim 27 is objected to because of the following informality: “anti-binding” should have been “antigen-binding”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 7 and 19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
The twice recitation of “a variant of that sequence having 1, 2 or 3 amino acid substitutions in the framework region” in claim 7 is ambiguous and indefinite because it is not clear if the “that sequence” is a variant from SEQ ID NO: 15 or SEQ ID NO: 16 or from other sequence. Accordingly, one of ordinary skill in the art would not reasonably be apprised of the metes and bounds of the invention. It is suggested that claim 7 be amended to recite “a variant thereof having 1, 2 or 3 amino acid substitutions in the framework region”.
Claim 19 recites the limitation "the " in claim 1. There is insufficient antecedent basis for this limitation in the claim.
Claim rejections under - 35 U.S.C. 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-5, 7, 19, 21 and 27 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 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The Written Description Guidelines for examination of patent applications indicates, “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, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical characteristics and/or other 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 applicant was in possession of the claimed genus.” (see MPEP 2163).
Claim 1 encompasses any antigen-binding fragment that specifically binds any FcγRIIA, wherein the antigen-binding fragment comprises any heavy chain variable region, any light chain variable region and any linker, and wherein at least a portion of the linker binds FcγRIIA.
Claim 2 encompasses the antigen-binding fragment according to claim l, wherein the heavy chain variable region and the light chain variable region are joined by the linker.
Claim 3 encompasses the antigen-binding fragment according to claim 1 or claim 2, wherein the antigen-binding fragment comprises:
a heavy chain variable region comprising: a) a heavy chain CDR1 with an amino acid sequence according to SEQ ID NO: 4; b) a heavy chain CDR2 with an amino acid sequence according to SEQ ID NO: 5; c) a heavy chain CDR3 with an amino acid sequence according to SEQ ID NO: 6; and
a light chain variable region comprising: d) a light chain CDR1 with an amino acid sequence according to SEQ ID NO: 7; e) a light chain CDR2 with an amino acid sequence according to SEQ ID NO: 8; and f) a light chain CDR3 with an amino acid sequence according to SEQ ID NO: 9.
Claim 4 encompasses the antigen-binding fragment according to claim 1, wherein the linker comprises the amino acid sequence: WAW X1WX2TETX3V and wherein: X1 is selected from V or A; X2 is selected from L or A; and X3 is selected from A or G.
Claim 5 encompasses the antigen-binding fragment according to claim 1 any one of claims 1 to 4, wherein the linker comprises: any amino acid sequence with at least 90% sequence identity to SEQ ID NO: 11; or an amino acid sequence according to SEQ ID NO: 11.
Claim 7 encompasses the antigen-binding fragment according to claim 1, wherein:
the heavy chain variable region comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 15;
the heavy chain variable region comprises an amino acid sequence according to SEQ ID NO:15, or a variant of that sequence having 1, 2, or 3 amino acid substitutions in the framework region;
the light chain variable region comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 16; and/or
the light chain variable region comprises an amino acid sequence according to SEQ ID NO:16, or a variant of that sequence having 1, 2, or 3 amino acid substitutions in the framework region.
Claim 19 encompasses the antigen-binding fragment according to claim 1, wherein: the antigen-binding fragment is a single-chain variable fragment (scFv);. and/or the functional linker is positioned adjacent to or within a flexible linker.
Claim 21 encompasses the antigen-binding fragment according to claim 19,wherein the flexible linker: comprises or consists of neutral amino acids;. and/or comprises or consists of between 1 and 15 amino acids, between 3 and 14 amino acids, between 3 and 14 amino acids, between 9 and 13 amino acids, between 10 and 12 amino acids, or 11 amino acids.
Claim 27 encompasses a pharmaceutical composition comprising the anti-binding fragment of claim 1.
The specification discloses murine and humanized scFv antibodies (HRU5 to HRU7) and linker wherein the sequences are shown in Table 1 as SEQ ID NO: 1-16. The scFvs are arranged VH-linker-VL.
HRU5: Humanized variable heavy and variable light chains derived from the IV.3 MoAb linked with a GGGGWAWVWLTETAVGGGGS linker (SEQ ID NO: 10).
HRU6: HRU5 linked to lepirudin (an anticoagulant peptide) by a SenGlyn linker.
HRU7: HRU5 linked to bivalirudin (an anticoagulant peptide) by a SenGlyn linker.
HRU5 to HRU7 are effective FcγRIIA blocking agents. In addition, HRU6 and HRU7 possess enhanced binding affinity for FcγRIIA and anticoagulant function.
However, the specification does not describe the structure, e.g., amino acid sequence of heavy chain variable region and light chain variable region for any and all antigen-binding fragment that correlated with binding to all possible FcγRIIA (claims 1-2, 4, 5, 19, 27). The specification does not describe a representative number of species falling within the scope of the genus or structural features common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of antigen-binding fragment that specifically binds any and all possible FcγRIIA. Given the lack of specific guidance as to the structure of any and all linker that binds to any FcγRIIA and antigen-binding fragment that specifically binds FcγRIIA, it is unpredictable which undisclosed antigen-binding fragment that binds FcγRIIA is effective as a pharmaceutical composition (claim 27) for treating any and all diseases.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 22:159-168, 2009; PTO 892; see, e.g., Discussion).
Similarly, Edwards et al., J Mol Biol. 334(1): 103-118, 2003; PTO 892 found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen (as held in Amgen), and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen (as held in Abbvie).
In Abbvie v. Centocor (Fed. Cir. 2014), the Court held that a disclosure of many different antibodies (in that case neutralizing antibodies to IL-12 with a particular binding affinity) was not enough to support the genus of all IL-12 neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
In this case, the specification discloses scFv antibodies comprise the same set of heavy chain CDR 1-3 of SEQ ID NO: 4-6 and light chain CDR 1-3 of SEQ ID NO: 7-9, see Table 1. This is not enough to support genus of antigen-binding fragment that specifically binds any and all possible FcγRIIA.
Regarding at least a portion of the linker binds FcγRIIA (claim 12), the specification discloses just one linker comprises the amino acids sequence GGGGWAWVWLTETAVGGGGS (SEQ ID NO: 10) that binds human FcγRIIA.
However, the specification does not describe the structure, e.g., amino acid sequence of the linker that binds any and all mammalian FcγRIIA to demonstrate possession of the genus at the time of filing.
Even assuming the linker comprises an amino acid sequence according to SEQ ID NO: 11 (claim 5), the specification discloses SEQ ID NO: 11 is WAWVWLTETAV. The phrase “an amino acid sequence” encompasses the full-length sequence as well as any fragment thereof. The specification does not describe a fragment of WAWVWLTETAV such as any two amino acids can link to a heavy chain variable region and a light chain variable region still maintains structural conformation and binds specifically to FcγRIIA.
Regarding the heavy chain variable region comprise an amino acid sequence according to SEQ ID NO: 15 and/or the light chain variable region comprises an amino acid sequence according to SEQ ID NO: 16 (claim 7), The phrase “an amino acid sequence” encompasses the full-length sequence as well as any fragment thereof. The specification does not describe which fragment, such as any two amino acids of heavy chain variable region of SEQ ID NO: 15 and which fragment of light chain variable region maintains antigen binding to FcγRIIA. Furthermore, the term “or” does not require light chain variable region comprising SEQ ID NO: 16. 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. It is unlikely that the antigen-binding fragment as defined by the claim, which may contain less than the full complement of CDRs from the heavy and light chain variable regions have the required binding function.
Regarding heavy chain comprising an amino sequence with at least 90% sequence identity to SEQ ID NO: 15 or light chain comprising an amino sequence with at least 90% sequence identity to SEQ ID NO: 16 (claim 7), the specification does not teach where and what amino acid within the full-length sequence of SEQ ID NO: 15 or SEQ ID NO: 16 to be substituted, added, deleted, or a combination thereof such that the modified heavy chain and modified light chain still maintains 3-D structure and binds FcγRIIA.
The art teach that amino acid substitutions within framework residues and antibody binding is unpredictable.
For example, Wu et al., (J Mol Biol 294: 151-162, 1999; PTO 892) state that, while certain residues have been identified as important for maintaining conformation, it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left col.).
Sela-Culang et al (Frontiers in Immunology 4: 302, 2013; PTO 892) teach that framework residues that affect antigen binding include those that make contact with the antigen or are in close proximity to the CDRs and those affect the orientation and conformation of the CDRs, impacting antigen binding indirectly, see para. 2 to 4. As such, the effect of framework residue mutations on antigen is unpredictable.
Dufner et al (Trends Biotechnol 24(11): 523-529, 2006; PTO 892) teaches "specific structural information-on the antibody to be optimized, its antigen and their interaction is rarely available or lacks the high resolution required to determine accurately important details such as side-chain conformations, hydrogen-bonding patterns and the position of water molecules, see page 527, paragraph 1, in particular). The specification does not define specific structural information detailing the number and exact position in the antibody heavy and light chain variable regions can be modified, which can vary considerably from case to case and therefore cannot be predicted (legend to Figure 2 of Dufner).
Thus even with the available screening approaches, one skill in the art still could not predict the hotspots much less those residues critical for conferring specific antigen binding for any of the variable domains absent further additional information or guidance. In view of all of the above, a skilled artisan would reasonably conclude that applicant was not in possession of the full breadth of the claimed genus of antigen-binding fragment that specifically binds FcγRIIA as a pharmaceutical composition at the time the instant invention was filed.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must 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.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Thus, the specification fails to describe these DNA sequences.
For genus claims, an adequate written description of a claimed genus requires more than a generic statement of an invention's boundaries. A patent must set forth either a representative number of species falling within the scope of the genus or structural features common to the members of the genus. Kubin, Exparte, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007); Ariad Pharms., Inc. v. Eli Lilly& Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010).
Therefore, only (1) a single chain antibody (ScFv) that binds human FcγRIIA, wherein the scFv comprises a heavy chain variable region comprising a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3, a light chain variable region comprising a light chain CDR1, a light chain CDR2 and a light chain CDR3 and a linker that binds to FcγRIIA, wherein the heavy chain CDR1 comprises the amino acid sequence according to SEQ ID NO: 4, the heavy chain CDR2 comprises the amino acid sequence according to SEQ ID NO: 5, the heavy chain CDR3 comprises the amino acid sequence according to SEQ ID NO: 6, the light chain CDR1 comprises the amino acid sequence according to SEQ ID NO: 7, the light chain CDR2 comprises the amino acid sequence according to SEQ ID NO: 8, the light chain CDR3 comprises the amino acid sequence according to SEQ ID NO: 8 and wherein the linker comprises the amino acid sequence of SEQ ID NO: 10, (2) the single chain antibody (ScFv) that binds FcγRIIA, wherein the scFv comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 12, 17, 18 and 19, (3) the single chain antibody (ScFv) above linked to bivalirudin comprising the amino acid sequence of SEQ ID NO: 14, but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112, first paragraph.
Claims 1-5, 7, 19, 21 and 27 are 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 (1) a single chain antibody (ScFv) that binds human FcγRIIA, wherein the scFv comprises a heavy chain variable region comprising a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3, a light chain variable region comprising a light chain CDR1, a light chain CDR2 and a light chain CDR3 and a linker that binds to FcγRIIA, wherein the heavy chain CDR1 comprises the amino acid sequence according to SEQ ID NO: 4, the heavy chain CDR2 comprises the amino acid sequence according to SEQ ID NO: 5, the heavy chain CDR3 comprises the amino acid sequence according to SEQ ID NO: 6, the light chain CDR1 comprises the amino acid sequence according to SEQ ID NO: 7, the light chain CDR2 comprises the amino acid sequence according to SEQ ID NO: 8, the light chain CDR3 comprises the amino acid sequence according to SEQ ID NO: 8 and wherein the linker comprises the amino acid sequence of SEQ ID NO: 10, (2) the single chain antibody (ScFv) that binds FcγRIIA, wherein the scFv comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 12, 17, 18 and 19, (3) the single chain antibody (ScFv) above linked to bivalirudin comprising the amino acid sequence of SEQ ID NO: 14, does not reasonably provide enablement for any antigen-binding fragment that specifically binds any FcγRIIA as set forth in claims 1-5, 7, 19, 21 and a pharmaceutical composition as set forth in claim 27. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. . In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claim 1 encompasses any antigen-binding fragment that specifically binds any FcγRIIA, wherein the antigen-binding fragment comprises any heavy chain variable region, any light chain variable region and any linker, and wherein at least a portion of the linker binds FcγRIIA.
Claim 2 encompasses the antigen-binding fragment according to claim l, wherein the heavy chain variable region and the light chain variable region are joined by the linker.
Claim 3 encompasses the antigen-binding fragment according to claim 1 or claim 2, wherein the antigen-binding fragment comprises:
a heavy chain variable region comprising: a) a heavy chain CDR1 with an amino acid sequence according to SEQ ID NO: 4; b) a heavy chain CDR2 with an amino acid sequence according to SEQ ID NO: 5; c) a heavy chain CDR3 with an amino acid sequence according to SEQ ID NO: 6; and
a light chain variable region comprising: d) a light chain CDR1 with an amino acid sequence according to SEQ ID NO: 7; e) a light chain CDR2 with an amino acid sequence according to SEQ ID NO: 8; and f) a light chain CDR3 with an amino acid sequence according to SEQ ID NO: 9.
Claim 4 encompasses the antigen-binding fragment according to claim 1, wherein the linker comprises the amino acid sequence: WAW X1WX2TETX3V and wherein: X1 is selected from V or A; X2 is selected from L or A; and X3 is selected from A or G.
Claim 5 encompasses the antigen-binding fragment according to claim 1 any one of claims 1 to 4, wherein the linker comprises: any amino acid sequence with at least 90% sequence identity to SEQ ID NO: 11; or an amino acid sequence according to SEQ ID NO: 11.
Claim 7 encompasses the antigen-binding fragment according to claim 1, wherein:
the heavy chain variable region comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 15;
the heavy chain variable region comprises an amino acid sequence according to SEQ ID NO:15, or a variant of that sequence having 1, 2, or 3 amino acid substitutions in the framework region;
the light chain variable region comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 16; and/or
the light chain variable region comprises an amino acid sequence according to SEQ ID NO:16, or a variant of that sequence having 1, 2, or 3 amino acid substitutions in the framework region.
Claim 19 encompasses the antigen-binding fragment according to claim 1, wherein: the antigen-binding fragment is a single-chain variable fragment (scFv);. and/or the functional linker is positioned adjacent to or within a flexible linker.
Claim 21 encompasses the antigen-binding fragment according to claim 19,wherein the flexible linker: comprises or consists of neutral amino acids;. and/or comprises or consists of between 1 and 15 amino acids, between 3 and 14 amino acids, between 3 and 14 amino acids, between 9 and 13 amino acids, between 10 and 12 amino acids, or 11 amino acids.
Claim 27 encompasses a pharmaceutical composition comprising the anti-binding fragment of claim 1.
The specification discloses murine and humanized scFv antibodies (HRU5 to HRU7) and linker wherein the sequences are shown in Table 1 as SEQ ID NO: 1-16. The scFvs are arranged VH-linker-VL.
HRU5: Humanized variable heavy and variable light chains derived from the IV.3 MoAb linked with a GGGGWAWVWLTETAVGGGGS linker (SEQ ID NO: 10).
HRU6: HRU5 linked to lepirudin (an anticoagulant peptide) by a SenGlyn linker.
HRU7: HRU5 linked to bivalirudin (an anticoagulant peptide) by a SenGlyn linker.
HRU5 to HRU7 are effective FcγRIIA blocking agents. In addition, HRU6 and HRU7 possess enhanced binding affinity for FcγRIIA and anticoagulant function.
However, the specification does not teach the structure, e.g., amino acid sequence of heavy chain variable region and light chain variable region for any and all antigen-binding fragment that correlated with binding to any and all possible FcγRIIA (claims 1-2, 4, 5, 19, 27). The specification does not teach a representative number of species falling within the scope of the genus or structural features common to the members of the genus so the one of skill in the art can make and use the genus of antigen-binding fragment that specifically binds any FcγRIIA wherein at least a portion of the linker binds FcγRIIA. There are insufficient in vivo working examples, it is unpredictable which undisclosed antigen-binding fragment that binds FcγRIIA is effective as a pharmaceutical composition (claim 27) for treating any and all diseases.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 22:159-168, 2009; PTO 892; see, e.g., Discussion).
Similarly, Edwards et al., (J Mol Biol. 334(1): 103-118, 2003; PTO 892) found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen, and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen.
Regarding at least a portion of the linker binds FcγRIIA (claim 12), the specification discloses just one linker comprises the amino acids sequence GGGGWAWVWLTETAVGGGGS (SEQ ID NO: 10).
However, the specification does not teach the structure, e.g., amino acid sequence of the linker that binds any and all mammalian FcγRIIA.
Even assuming the linker comprises an amino acid sequence according to SEQ ID NO: 11 (claim 5), the specification discloses SEQ ID NO: 11 is WAWVWLTETAV. The phrase “an amino acid sequence” encompasses the full-length sequence as well as any fragment thereof. The specification does not teach a fragment of WAWVWLTETAV such as any two amino acids linked to a heavy chain variable region and a light chain variable region still maintains structural conformation and binds FcγRIIA.
Regarding the heavy chain variable region comprise an amino acid sequence according to SEQ ID NO: 15 and/or the light chain variable region comprises an amino acid sequence according to SEQ ID NO: 16 (claim 7), The phrase “an amino acid sequence” encompasses the full-length sequence as well as any fragment thereof. The specification does not teach which fragment, such as any two amino acids of heavy chain variable region of SEQ ID NO: 15 and light chain variable region still maintains antigen binding to FcγRIIA.
Further, the term “or” does not require light chain variable region comprising SEQ ID NO: 16. 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. It is unlikely that the antigen-binding fragment as defined by the claim, which may contain less than the full complement of CDRs from the heavy and light chain variable regions have the required binding function.
Regarding heavy chain comprising an amino sequence with at least 90% sequence identity to SEQ ID NO: 15 or light chain comprising an amino sequence with at least 90% sequence identity to SEQ ID NO: 16 (claim 7), the specification does not teach where and what amino acid within the full-length sequence of SEQ ID NO: 15 or SEQ ID NO: 16 to be substituted, added, deleted, or a combination thereof such that the modified heavy chain and modified light chain variable regions still maintains 3-D structure and binds FcγRIIA.
The art teach that amino acid substitutions within framework residues and antibody binding is unpredictable.
For example, Wu et al., (J Mol Biol 294: 151-162, 1999; PTO 892) state that, while certain residues have been identified as important for maintaining conformation, it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left col.).
Sela-Culang et al (Frontiers in Immunology 4: 302, 2013; PTO 892) teach that framework residues that affect antigen binding include those that make contact with the antigen or are in close proximity to the CDRs and those affect the orientation and conformation of the CDRs, impacting antigen binding indirectly, see para. 2 to 4. As such, the effect of framework residue mutations on antigen is unpredictable.
Dufner et al., (Trends Biotechnol 24(11): 523-529, 2006; PTO 892) teaches "specific structural information-on the antibody to be optimized, its antigen and their interaction is rarely available or lacks the high resolution required to determine accurately important details such as side-chain conformations, hydrogen-bonding patterns and the position of water molecules, see page 527, paragraph 1, in particular). The specification does not define specific structural information detailing the number and exact position in the antibody heavy and light chain variable regions can be modified, which can vary considerably from case to case and therefore cannot be predicted (legend to Figure 2 of Dufner). Thus even with the available screening approaches, one skill in the art still could not predict the hotspots much less those residues critical for conferring specific antigen binding for any of the variable domains absent further additional information or guidance.
There are insufficient in vivo working example, it is unpredictable which undisclosed antigen-binding fragment is effective as a pharmaceutical composition (claim 27) for treating any and all diseases.
In view of the quantity of experimentation necessary, the limited working examples, the unpredictability of the art, the lack of sufficient guidance in the specification, and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 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 1, 2, 4, 5, 19, 21, 27 are rejected under 35 U.S.C. 103 as being unpatentable over Van De Winkel (US20070253958, published November 1, 2007; PTO 892) in view of US Patent No. 9,636,415 (issued May 2, 2017; PTO 892).
Claim 1 encompasses a antigen-binding fragment that specifically binds FcγRIIA, wherein the antigen-binding fragment comprises any heavy chain variable region, any light chain variable region and any linker, and wherein at least a portion of the linker binds FcγRIIA.
Claim 2 encompasses the antigen-binding fragment according to claim l, wherein the heavy chain variable region and the light chain variable region are joined by the linker.
Claim 4 encompasses the antigen-binding fragment according to claim 1, wherein the linker comprises the amino acid sequence: WAW X1WX2TETX3V and wherein: X1 is selected from V or A; X2 is selected from L or A; and X3 is selected from A or G.
Claim 5 encompasses the antigen-binding fragment according to claim 1 any one of claims 1 to 4, wherein the linker comprises: any amino acid sequence with at least 90% sequence identity to SEQ ID NO: 11; or an amino acid sequence according to SEQ ID NO: 11.
Claim 19 encompasses the antigen-binding fragment according to claim 1, wherein: the antigen-binding fragment is a single-chain variable fragment (scFv);. and/or the functional linker is positioned adjacent to or within a flexible linker.
Claim 21 encompasses the antigen-binding fragment according to claim 19,wherein the flexible linker: comprises or consists of neutral amino acids;. and/or comprises or consists of between 1 and 15 amino acids, between 3 and 14 amino acids, between 3 and 14 amino acids, between 9 and 13 amino acids, between 10 and 12 amino acids, or 11 amino acids.
Claim 27 encompasses a pharmaceutical composition comprising the anti-binding fragment of claim 1.
Regarding claims 1, 2, 19, Van De Winkel teaches an antigen-binding fragment, e.g., scFv (see para. [0118]) that binds human Fc.gamma.RIIA (CD32, see para. [0008]) wherein the scFv comprises a heavy chain variable region (VH) and a light chain variable region (VL) linked by a synthetic linker or flexible linker, e.g., (Gly.sub.4-Ser).sub.3, , see para. [0118], [0271], [0274], in particular.
Regarding claim 21, Van De Winkel teaches the flexible linker (Gly.sub.4-Ser).sub.3 comprises 15 neutral amino acid acids, see para. [0271].
Regarding claim 27, Van De Winkel teaches pharmaceutical composition comprising the reference antibody and a pharmaceutically acceptable carrier, see para. [0080].
Van De Winkel does not teach at least a portion of the linker binds FcγRIIA as per claim 1 wherein the linker comprises the amino acid sequence: WAW X1WX2TETX3V and wherein: X1 is V; X2 is L; and X3 is A as per claim 4 or wherein the linker comprises: any amino acid sequence with at least 90% sequence identity to SEQ ID NO: 11; or an amino acid sequence according to SEQ ID NO: 11 as per claim 5.
However, the ‘415 patent teaches FcγRIIA binding peptide comprises the amino acid sequence ADGAWAWVWLTETAVGAAK (SE ID NO: 68) and flexible linker wherein the reference peptide is 100% identical to the claimed SEQ ID NO: 11 as per claims 4-5, see col. 53, sequence alignment below:
Query Match 100.0%; Score 68; Length 19;
Best Local Similarity 100.0%;
Matches 11; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 WAWVWLTETAV 11
|||||||||||
Db 5 WAWVWLTETAV 15
The term “comprises” is open ended. It expands the peptide to include additional amino acids at either or both ends. The ‘415 patent teaches that the linkages between the different parts may be different and the advantage of genetic fusion of such setup is the flexibility in production, see col. 5, line 12-17. The ‘415 patent further teaches the binding part can be antibodies, or antibody fragments (such as Fab, Fv, scFv, dAb, F(Ab)2, minibody, etc., Antibodies and antibody fragments and derivatives may be generated and selected for binding to TLR9 and/or CD32 according to known methods such as hybridoma technology, B-cell cloning, phage display, ribosome display or cell surface display of antibody libraries, array screening of variant antibodies, including human and humanized antibodies, see col. 6, lines 11-20, col. 8, line 12-37, in particular. Example of antigen binding fragment that binds to CD32a from mAb IV.3 comprises the amino acid sequence of SEQ ID NO: 67, see col. 39, in particular. The ‘’415 patent teaches the flexible linker maybe any linker, see col. 40, line 2, in particular.
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the teachings of Van De Winkel and the ‘415 patent by linking the VH and VL that binds to FcγRIIA of Van De Winkel with the peptide that binds to FcγRIIA as a linker of the ‘415 patent to arrive at the claimed invention with a reasonable expectation of success, e.g., bivalent antigen-binding fragment scFv that binds to human FcγRIIA.
One of ordinary skill in the art would have been motivated to do so because the ‘415 patent teaches that the flexible linker may be any linker and the anti-CD32a peptide ADGAWAWVWLTETAVGAAK is known in the art and can be used for targeted to CD32a, see col. 53, line 19-21.
One of ordinary skill in the art would be motivated to do so in order to increase the valency (e.g., binding site) and avidity of the scFv for binding to human FcγRIIA (aka CD32a) on platelets thereby inhibits platelet aggregation for treating thrombogenic related disease.
“The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Claims 3 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Van De Winkel (US20070253958, published November 1, 2007; PTO 892) in view of US Patent No. 9,636,415 (issued May 2, 2017; PTO 892) as applied to claims 1, 2, 4, 5, 19, 21, 27 mentioned above and further in view of US Patent No. 9,382,321 (issued July 5, 2016; PTO 892).
The combine teachings of Van De Winkel and the ‘415 patent have been discussed supra.
The references above do not teach the antigen-binding fragment comprises:
a heavy chain variable region comprising: a) a heavy chain CDR1 with an amino acid sequence according to SEQ ID NO: 4; b) a heavy chain CDR2 with an amino acid sequence according to SEQ ID NO: 5; c) a heavy chain CDR3 with an amino acid sequence according to SEQ ID NO: 6; and
a light chain variable region comprising: d) a light chain CDR1 with an amino acid sequence according to SEQ ID NO: 7; e) a light chain CDR2 with an amino acid sequence according to SEQ ID NO: 8; and f) a light chain CDR3 with an amino acid sequence according to SEQ ID NO: 9 as per claim 3, wherein the heavy chain variable region comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 15; the light chain variable region comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 16 as per claim 7.
However, regarding claim 3, the ‘321 patent teaches anti-CD32a antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 32, which comprises the claimed heavy chain CDR1-3 of SEQ ID NO: 4-6, respectively, see sequence alignment below.
Qy 1 NYGMN--------------WLNTYTGESIYPDDFKG------------------------ 22
||||| |||||||||||||||||
Db 31 NYGMNWVKQAPGKGLKWMGWLNTYTGESIYPDDFKGRFAFSSETSASTAYLQINNLKNED 90
Qy 23 --------GDYGYDDPLDY 33
|||||||||||
Db 91 MATYFCARGDYGYDDPLDY 109
and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 41, which comprises the claimed light chain CDR1-3 of SEQ ID NO: 5-9, respectively, see sequence alignment below.
Query Match 85.0%; Score 140.3; Length 112;
Best Local Similarity 40.5%;
Matches 32; Conservative 0; Mismatches 0; Indels 47; Gaps 2;
Qy 1 RSSKSLLHTNGNTYLH---------------RMSVLAS---------------------- 23
|||||||||||||||| |||||||
Db 24 RSSKSLLHTNGNTYLHWYLQKPGQSPQLLIYRMSVLASGVPDRFSGSGSGTDFTLKISRV 83
Qy 24 ----------MQHLEYPLT 32
|||||||||
Db 84 EAEDVGVYYCMQHLEYPLT 102
Regarding claim 7, the ‘321 patent teaches the heavy chain variable region comprising SEQ ID NO: 32, which is 96.6% identical to the claimed SEQ ID NO: 15, see sequence alignment below:
Query Match 96.6%; Score 625; Length 120;
Best Local Similarity 94.9%;
Matches 112; Conservative 4; Mismatches 2; Indels 0; Gaps 0;
Qy 1 EVQLVESGPELKKPGETVKISCKASGYTFTNYGMNWVKQAPGKGLKWMGWLNTYTGESIY 60
::|||:||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QIQLVQSGPELKKPGETVKISCKASGYTFTNYGMNWVKQAPGKGLKWMGWLNTYTGESIY 60
Qy 61 PDDFKGRFAFSLETSASTAYLQINNLKSEDTATYFCARGDYGYDDPLDYWGQGTSVTV 118
||||||||||| |||||||||||||||:|| |||||||||||||||||||||||||||
Db 61 PDDFKGRFAFSSETSASTAYLQINNLKNEDMATYFCARGDYGYDDPLDYWGQGTSVTV 118
And wherein the light chain variable region comprising SEQ ID NO: 51, which is 93.6% identical to the claimed SEQ ID NO: 16, see sequence alignment below:
Query Match 93.6%; Score 557; Length 219;
Best Local Similarity 93.8%;
Matches 106; Conservative 4; Mismatches 3; Indels 0; Gaps 0;
Qy 1 DIVMTQAPPSVPVTPGESVSISCRSSKSLLHTNGNTYLHWFLQKPGQSPRLLIYRMSVLA 60
||||||| |||||||||||||||||||||||||||||||||||:|||||:||||||||||
Db 1 DIVMTQAAPSVPVTPGESVSISCRSSKSLLHTNGNTYLHWFLQRPGQSPQLLIYRMSVLA 60
Qy 61 SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQHLEYPLTFGAGTKLEIKR 113
|||||||||||||| ||| |||||||||||:|||||||||||||||||||:||
Db 61 SGVPDRFSGSGSGTAFTLSISRVEAEDVGVFYCMQHLEYPLTFGAGTKLELKR 113
The ‘321 patent teaches that administration of native anti-CD32a antibodies in vivo cause adverse reactions that include thrombocytopenia, drop in body temperature, and symptoms of shock. The inventors have found that administering effector-deficient anti-CD32a antibodies alleviates these adverse reactions, see Summary of invention, in particular.
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the teachings of Van De Winkel and the ‘415 patent in view of the ‘321 patent by substituting the VH and VL in the scFv that binds to FcγRIIA of Van De Winkel and the ‘415 patent for the VH and VL that binds to FcγRIIA as taught by the ‘321 patent to arrive at the claimed invention with a reasonable expectation success, e.g., treating CD32a-mediated disease or disorder in a human subject.
One of ordinary skill in the art would have been motivated to do so because the ‘321 patent teaches that the effector-deficient anti-CD32a antibodies do not cause thrombocytopenia, drop in body temperature, and symptoms of shock when treating CD32a-mediated disease in human subject.
In this case, simple substitution of one known element for another would obtain predictable results. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-5, 7, 19, 21 and 27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, 6, 16, 17 of copending Application No. 17/442,791 (hereinafter reference) in view of US Patent No. 9,636,415 (issued May 2, 2017; PTO 892). Although the claims at issue are not identical, they are not patentably distinct from each other because copending claims recite:
1. (Previously Presented) An antigen-binding fragment comprising heavy chain and light chain variable regions joined by a flexible-linker region, wherein the antigen-binding fragment prevents activation of platelets by either blocking FcRIIa binding on platelets, neutrophils and monocytes or neutralising platelet factor 4, wherein: (i) the antigen-binding fragment comprises: a heavy chain variable region comprising:
(a) a heavy chain CDR1 sequence according to SEQ ID NO: 3; (b) a heavy chain CDR2 sequence according to SEQ ID NO: 4; (c) a heavy chain CDR3 sequence according to SEQ ID NO: 5;
wherein said heavy chain variable region comprises at least 90% sequence identity to SEQ ID NO: 13, and a light chain variable region comprising: (a) a light chain CDR1 sequence according to SEQ ID NO: 6, which corresponds to instant claim 3;
(b) a light chain CDR2 sequence according to SEQ ID NO: 7; and (c) a light chain CDR3 sequence according to SEQ ID NO: 8; wherein said light chain variable region comprises at least 90% sequence identity to SEQ ID NO: 14, wherein the antigen-binding fragment is conjugated to bivalirudin or lepirudin; or (ii) the antigen-binding fragment comprises: a heavy chain variable region comprising: (a) a heavy chain CDR1 sequence according to SEQ ID NO: 16; (b) a heavy chain CDR2 sequence according to SEQ ID NO: 17;
(c) a heavy chain CDR3 sequence according to SEQ ID NO: 18; wherein said heavy chain variable region comprises at least 90% sequence identity to SEQ ID NO: 22, and a light chain variable region comprising: (a) a light chain CDR1 sequence according to SEQ ID NO: 19; (b) a light chain CDR2 sequence according to SEQ ID NO: 20; and (c) a light chain CDR3 sequence according to SEQ ID NO: 21; wherein said light chain variable region comprises at least 90% sequence identity to SEQ ID NO: 23.
2. (Previously Presented) The antigen-binding fragment of claim 1, wherein the fragment specifically binds to FcRIIa, and wherein the antigen-binding fragment comprises: a heavy chain variable region comprising:
(a) a heavy chain CDR1 sequence according to SEQ ID NO: 3;
(b) a heavy chain CDR2 sequence according to SEQ ID NO: 4;
(c) a heavy chain CDR3 sequence according to SEQ ID NO: 5;
wherein said heavy chain variable region comprises at least 90% sequence identity to SEQ ID NO: 13, and
a light chain variable region comprising:
(a) a light chain CDR1 sequence according to SEQ ID NO: 6;(b) a light chain CDR2 sequence according to SEQ ID NO: 7; and(c) a light chain CDR3 sequence according to SEQ ID NO: 8; wherein said light chain variable region comprises at least 90% sequence identity to SEQ ID NO: 14, which corresponds to instant claim 7.
4. (Original) The antigen-binding fragment according to claim 2, wherein:
(a) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 13, or a variant of that sequence having 1, 2, or 3 amino acid substitutions in the framework region; and/or
(b) the light chain variable region of SEQ ID NO:14, or a variant of that sequence having 1, 2, or 3 amino acid substitutions in the framework region, which corresponds to instant claim 7.
6. (Previously Presented) The antigen binding fragment of claim 1, wherein the flexible-linker region is an oligopeptide having an amino acid sequence as set forth in SEQ ID NO:9, which corresponds to instant claim 2.
10. (Previously Presented) The antigen-binding fragment according to claim 2, which comprises: (i) the amino acid sequence of SEQ ID NO: 10, or a variant of that sequence having 1, 2, or 3 amino acid substitutions in the framework region; or (ii) the amino acid sequence of SEQ ID NO: 11, or a variant of that sequence having 1, 2, or 3 amino acid substitutions in the framework region.
16. (Previously Presented) The antigen-binding fragment according to claim 1, wherein the antigen- binding fragment is a scFv, which corresponds to instant claim 19.
17. (Previously Presented) A pharmaceutical composition comprising the anti-binding fragment of claim 1, which corresponds to instant claim 27.
18/247,381
17/442,791
SEQ ID NO: 4
NYGMN
NYGMN (SEQ ID NO: 3)
SEQ ID NO: 5
WLNTYTGESIYPDDFKG
WLNTYTGESIYPDDFKG (SEQ ID NO: 4)
SEQ ID NO: 6
GDYGYDDPLDY
GDYGYDDPLDY (SEQ ID NO: 5)
SEQ ID NO: 7
RSSKSLLHTNGNTYLH
RSSKSLLHTNGNTYLH
(SEQ ID NO: 6)
SEQ ID NO: 8
RMSVLAS
RMSVLAS
(SEQ ID NO: 7)
SEQ ID NO: 9
MQHLEYPLT
MQHLEYPLT
(SEQ ID NO: 8)
The reference humanized scFv comprises the amino acid sequence of SEQ ID NO: 12 comprises the claimed heavy chain CDRs 1-3 of SEQ ID NO: 4-6, respectively, see sequence alignment below:
Query Match 87.6%; Score 173.4; Length 259;
Best Local Similarity 41.8%;
Matches 33; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 NYGMN--------------WLNTYTGESIYPDDFKG------------------------ 22
||||| |||||||||||||||||
Db 31 NYGMNWVKQAPGKGLKWMGWLNTYTGESIYPDDFKGRFAFSLETSASTAYLQINNLKSED 90
Qy 23 --------GDYGYDDPLDY 33
|||||||||||
Db 91 TATYFCARGDYGYDDPLDY 109
The reference humanized scFv comprises the amino acid sequence of SEQ ID NO: 14 comprises the claimed light chain CDRs of SEQ ID NO: 7-9, respectively, see sequence alignment below:
Query Match 87.6%; Score 173.4; Length 259;
Best Local Similarity 41.8%;
Matches 33; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 NYGMN--------------WLNTYTGESIYPDDFKG------------------------ 22
||||| |||||||||||||||||
Db 31 NYGMNWVKQAPGKGLKWMGWLNTYTGESIYPDDFKGRFAFSLETSASTAYLQINNLKSED 90
Qy 23 --------GDYGYDDPLDY 33
|||||||||||
Db 91 TATYFCARGDYGYDDPLDY 109
The reference SEQ ID NO: 13 is identical to the claimed SEQ ID NO: 15, see sequence alignment below:
OTHER INFORMATION: Humanised ScFv heavy chain variable region
Query Match 100.0%; Score 647; Length 118;
Best Local Similarity 100.0%;
Matches 118; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGPELKKPGETVKISCKASGYTFTNYGMNWVKQAPGKGLKWMGWLNTYTGESIY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGPELKKPGETVKISCKASGYTFTNYGMNWVKQAPGKGLKWMGWLNTYTGESIY 60
Qy 61 PDDFKGRFAFSLETSASTAYLQINNLKSEDTATYFCARGDYGYDDPLDYWGQGTSVTV 118
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 PDDFKGRFAFSLETSASTAYLQINNLKSEDTATYFCARGDYGYDDPLDYWGQGTSVTV 118
The reference SEQ ID NO: 14 is identical to the claimed SEQ ID NO: 16, see sequence alignment below:
OTHER INFORMATION: Humanised ScFv light chain variable region
Query Match 100.0%; Score 595; Length 124;
Best Local Similarity 100.0%;
Matches 114; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIVMTQAPPSVPVTPGESVSISCRSSKSLLHTNGNTYLHWFLQKPGQSPRLLIYRMSVLA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIVMTQAPPSVPVTPGESVSISCRSSKSLLHTNGNTYLHWFLQKPGQSPRLLIYRMSVLA 60
Qy 61 SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQHLEYPLTFGAGTKLEIKRA 114
||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQHLEYPLTFGAGTKLEIKRA 114
The reference does not teach at least a portion of the linker binds FcγRIIA as per claim 1 wherein the linker comprises the amino acid sequence: WAW X1WX2TETX3V and wherein: X1 is V or A; X2 is L; and X3 is A as per claim 4 or wherein the linker comprises: any amino acid sequence with at least 90% sequence identity to SEQ ID NO: 11; or an amino acid sequence according to SEQ ID NO: 11 as per claim 5.
However, the ‘415 patent teaches FcγRIIA binding peptide comprises the amino acid sequence ADGAWAWVWLTETAVGAAK (SE ID NO: 68) and flexible linker wherein the reference peptide is 100% identical to the claimed SEQ ID NO: 11 as per claims 4-5, see col. 53, sequence alignment below:
Query Match 100.0%; Score 68; Length 19;
Best Local Similarity 100.0%;
Matches 11; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 WAWVWLTETAV 11
|||||||||||
Db 5 WAWVWLTETAV 15
The term “comprises” is open ended. It expands the peptide to include additional amino acids at either or both ends. The ‘415 patent teaches that the linkages between the different parts may be different and the advantage of genetic fusion of such setup is the flexibility in production, see col. 5, line 12-17. The ‘415 patent further teaches the binding part can be antibodies, or antibody fragments (such as Fab, Fv, scFv, dAb, F(Ab)2, minibody, etc., Antibodies and antibody fragments and derivatives may be generated and selected for binding to TLR9 and/or CD32 according to known methods such as hybridoma technology, B-cell cloning, phage display, ribosome display or cell surface display of antibody libraries, array screening of variant antibodies, including human and humanized antibodies, see col. 6, lines 11-20, col. 8, line 12-37, in particular. Example of antigen binding fragment that binds to CD32a from mAb IV.3 comprises the amino acid sequence of SEQ ID NO: 67, see col. 39, in particular. The ‘’415 patent teaches the flexible linker maybe any linker, see col. 40, line 2, in particular.
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the teachings of reference and the ‘415 patent by linking the VH and VL that binds to FcγRIIA of reference with the peptide that binds to FcγRIIA as a linker of the ‘415 patent to arrive at the claimed invention with a reasonable expectation of success, e.g., bivalent antigen-binding fragment scFv that binds to human FcγRIIA for improving avidity of the antibody. One of ordinary skill in the art would have been motivated to do so because the ‘415 patent teaches that the flexible linker may be any linker and the anti-CD32a peptide ADGAWAWVWLTETAVGAAK is known in the art and can be used for targeted to CD32a, see col. 53, line 19-21. One of ordinary skill in the art would be motivated to do so in order to increase the valency of the scFv for binding to human FcγRIIA (aka CD32a).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Allowable Subject Matter
SEQ ID NO: 10, 14, 15, 17, 18, 19, and 20 are free of prior art.
Conclusion
No claim is allowed.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641
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