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 .
Claim Interpretation
For the purposes of examination, claims 61 is interpreted as encompassing the specifically recited antibody clones and variants thereof comprising VH and VL sequences derived from those clones, wherein the VH and VL sequences retain at least 80% sequence identity to the corresponding reference sequences. Because the specification identifies the recited clones as antibodies that target HLA-E-VL9, the claim is also interpreted as referring to antibody variants that are intended to bind to HLA-E host peptide complexes, rather than referring to unrelated antibodies binding to unrelated targets. However, as presently written, claim 61 raises issues under both 35 U.S.C. 112(a) and 35 U.S.C. 112(b) as discussed further below.
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/PatentLegalFramework), 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 – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Several amino acid sequences appearing in the specification are not identified by a sequence identifier, including in Para. 0010, Para. 0016, Para. 0046-0047, Para. 0083, Para. 0086, Para. 0097, Para. 0112, Para. 0116, Para. 0265, Para. 270, Para. 0275, Para. 0290, Para. 0299, Para. 0301, Para. 0303, Para. 0379, and Para. 0381. Other examples in the specification may be present, and Applicant is requested to verify that any nucleotide/amino acid sequences appearing in the specification is identified by a sequence identifier.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).. Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings. Several figures have amino acid sequences that are not identified by a sequence identifier, including Fig. 1A, 1G, 1E, 2J, 5L, 6B, 7A-7K, 11, 12J, 12K, 19, 21E, 21F, 23, 24A, 26C. Other examples in the drawings may be present, and Applicant is requested to verify that any nucleotide/amino acid sequences appearing in the drawings is identified by a sequence identifier.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 61-63, 79-83, 85, 86, 87, 88, 94, and 99 are rejected under 35 U.S.C. 101 because the claimed invention is directed to products of nature without significantly more. The claims recite a recombinant antibody or fragment thereof selected from a group consisting of naturally-occurring murine and human HLA-E-VL9-specific antibodies, wherein the antibody or fragment comprises VH and VL chains having at least 80% sequence identity to the VH and VL sequences of the recited antibody clones. In particular, clones 3H4, CA147, 13F11,1OC10, 2D6, CA 18, CA119, CA120, CA122, CA123, CA124, CA125, CA127, CA128, CA129, CA130, CA131, CA132, CA133, CA134, CA135, CA136, CA137, CA138, CA139, CA140, CA141, CA143, CA144, CA145, CA146, CA401, 3H4 Gv2, 3H4 Gv3, 3H4 Gv4, 3H4 Gv5, 3H4 Gv6, 3H4 Gv7, 3H4 Gv8, 3H4 Gv9, 3H4 Gv10, 3H4 Gv11, and 3H4 Gv12 were isolated from the naive IgM B cell BCR repertoire in mice or in non-immunized, HCMV seronegative male humans (Para. 0275 of Examples, Para. 0292 of Examples, Discussion on Para. 0301). Thus, these clones are naturally-occurring and represent products of nature. This judicial exception is not integrated into a practical application because the additional claim elements do not impose meaningful structural limitations that distinguish the claimed antibodies or antibody fragments from their naturally-occurring counterparts. In particular, the limitation requiring VH and VL chains having at least 80% sequence identity encompasses antibodies having VH and VL sequences that are 100% identical to the naturally-occurring VH and VL sequences of the recited clones. Thus, the claim currently under examination either recites biological sequences which are identical to that of the naturally occurring antibodies or are generic enough that they reasonably encompass the naturally occurring antibody. Further, the term “recombinant” describes the manner in which the antibody may be produced but does not, by itself, require a structural difference between a recombinant antibody and naturally-occurring antibodies encompassed by the claims. The dependent claims also do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional limitations merely recite features that are inherent in the naturally-occurring antibody product. For example, reciting that the antibody comprises an Fc region (claim 83) does not add significantly more because the naturally-occurring full-length murine and human antibodies inherently comprise Fc regions. Similarly, reciting that the antibody may be of any isotype (claim 86) merely encompasses the isotypes (e.g. IgM) of the recited naturally-occurring antibody clones. A recombinant antibody formatted as “a purified antibody” (claim 85) still reads on an antibody that is identical to one of the naturally-occurring antibody clones. The limitations directed to pharmaceutical compositions, pharmaceutically acceptable carriers, excipients, or diluents (claims 94 and 99) merely combine the naturally-occurring antibody with conventional/routine formulation components and do not impart a marked difference to the claimed antibody. Lastly, the limitations directed to use of the antibody as a medicament (claim 87) or for treatment/prevention of HLA-E-expressing tumor (claim 88) merely recite the intended use of the naturally-occurring antibody and do not alter the structural identity of the claimed product. Therefore, the claims do not recite additional limitations that alter the structure of naturally-occurring murine and human HLA-E-VL9 specific antibodies and thus do not encompass an inventive concept.
Claims 89, 90, and 95 are also rejected under 35 U.S.C. 101 because the claimed invention is directed to products of nature without significantly more. The claims recite a nucleic acid or ribonucleic acid comprising a nucleic acid sequence encoding the recombinant antibody or fragment thereof of claim 61. The claim thus encompasses naturally-occurring nucleic acid sequences encoding the naturally-occurring antibody clones. This judicial exception is not integrated into a practical application because the additional claim elements do not impose meaningful structural limitations that distinguish the claimed antibodies or antibody fragments from their naturally-occurring counterparts. Claims 89, 90, and 95 incorporate the limitations of claim 1; and as stated above, the limitation requiring VH and VL chains of the recombinant antibody to have least 80% sequence identity encompasses antibodies having VH and VL sequences that are 100% identical to the naturally-occurring sequences of the recited clones. Further, the term “recombinant” describes the manner in which the antibody may be produced but does not, by itself, require a structural difference between a recombinant antibody and naturally-occurring antibodies encompassed by the claims. Additionally, the limitation of “a pharmaceutical composition” (claim 95) is a statement of intended use and does not impart any marked difference to the claimed nucleic acids. Therefore, the claims do not recite additional limitations that alter the structure of a naturally-occurring nucleic acid encoding the naturally-occurring murine and human HLA-E-VL9 specific antibodies and thus do not encompass an inventive concept.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Claims 61-72 and 74-99 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 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.
Claim 61 is directed to several antibody clones that bind to HLA-E host peptide complexes, wherein each antibody clone comprises a heavy chain variable (VH) and a light chain variable (VL) region having at least 80% sequence identity to the referenced sequences. As such, the claim encompasses antibodies having random, undefined amino acid mutations, including in the CDR domains. However, there is no guidance provided in the specification determining which specific amino acid mutations can be made, particularly in the CDR domains, that predictably result in retention of binding to the target antigen. Claims 62-64, 68, 69, 79, 81-99 incorporate the limitations of claim 61 but do not cure the deficiencies of claim 61 and are thus also rejected.
Similarly, claim 70 recites a humanized antibodies selected from several antibody clones, wherein each clone comprises VH and VL chains having CDRs that are at least 80% identical to CDRs present in the parent sequence. As presently written, claim 70 thus encompasses antibody variants comprising CDRs having random, undefined amino acid mutations which can impact antigen binding.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by 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 genus (MPEP 2163).
In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin [e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
The court has further stated that “Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Id. at 1566, 43 USPQ2d at 1404 (quoting at 1171, 25 USPQ2d at 1606). Also see (CAFC 2002). Enzo-Biochem v. Gen-Probe Fiers, 984 F.2d 01-1230.
Claim 61 is directed to several antibody clones that bind to HLA-E host peptide complexes, wherein each antibody clone comprises a heavy chain variable (VH) and a light chain variable (VL) region having at least 80% sequence identity to the referenced sequences. As such, the claim encompasses antibodies having random, undefined amino acid mutations, including in the CDR domains.
The specification teaches the isolation and characterization of HLA-E-VL9 peptide complex-specific antibodies derived from the naive IgM B cell BCR repertoire in mice as well as in non-immunized, HCMV seronegative male humans (Para. 0275 of Examples, Para. 0292 of Examples, Discussion on Para. 0301). Several affinity-matured variants of the murine monoclonal antibody (mAb) 34H (3H4 Gvl to 3H4 Gvl2) having mutations at positions 97-100 of the CDR-H3 loop were also generated from an scFv library (Para. 0290 of Examples). The amino acid sequences for the HLA-E-VL9-specific murine and human antibodies, including any respective variants, are disclosed or identified in, e.g. Claim 61 and Figures 8A-8H.
As presently written, however, claim 61 recites partially defined VH and VL chains of each antibody clone in which at most 20% of the amino acid sequences can vary. Such variation can occur by amino acid substitution, deletion, or insertion and can be made in the CDRs of the antibodies; yet, there is no guidance provided in the specification about the type of amino acid mutations that can be made in the VH and/or VL chains of the antibodies –particularly in the CDR sequences – such that the ability of the antibody to bind to HLA-E-VL9 peptide complex is retained.
It is well-known in the art that amino acid substitutions in the CDR domains of an antibody can negatively impact binding activity (see, e.g. Piche-Nicholas et al, see in particular, Abstract; Colman, see entire document particularly Page 33, Col. 2; and Rudikoff et al, see Abstract). Thus, even a single amino acid substitution at a critical residue can significantly reduce or abolish binding to target antigen. Taken together, the effect of amino acid mutations on antibody binding affinity is not readily predictable. The level of skill and knowledge in the art is such that one of ordinary skill would not be able to readily identify without further testing which amino acid mutations can be made in the VH and VL sequences of the recited antibody clones—particularly in the CDR sequences— such that the ability of the antibodies to bind to target antigen is retained. Claims 62-69, 79, 81-99 incorporate the limitations of claim 61 but do not cure the deficiencies of claim 61 because they still encompass antibody variants having undefined amino acid mutations in the CDR domains that can negatively impact antigen binding. Thus, claims 62-69, 79, and 81-99 are also rejected.
Similarly, claim 70 recites a humanized antibody selected from a group consisting of 3H4, 13F11, 1OC10, 2D6, 3H4 Gv2, 3H4 Gv3, 3H4 Gv4, 3H4 Gv5, 3H4 Gv6, 3H4 Gv7, 3H4 Gv8, 3H4 Gv9, 3H4 Gv10, 3H4 Gv11, 3H4 Gv12, 3H4hexa, and 3H4sortaNP, wherein each clone comprises VH and VL chains having CDRs that are at least 80% identical to CDRs present in the parent sequence. As presently written, claim 70 thus encompasses antibody variants comprising CDRs in which at most 20% of the amino acid sequences can vary. Such variation can occur by amino acid substitution, deletion, or insertion. However, there is no guidance provided in the specification about the type of amino acid mutations that can be made in the CDR domains such that the ability of the antibody to bind to HLA-E-VL9 peptide complex is retained. Claims 71, 72, 74-78, 80 depend incorporate the limitations of claim 70 but do not cure the deficiencies of claim 70 because they still encompass antibody variants having undefined amino acid mutations in the CDR domains that can negatively impact antigen binding. Thus, claims 71, 72, 74-78, 80 are also rejected.
Therefore, the claimed genus of HLA-E peptide complex specific antibodies lacks adequate written description because there does not appear to be any correlation between the structure of the claimed antibodies having random undefined amino acid mutations in the CDR domains and the function of binding to target antigen. Thus, one of ordinary skill in the art would reasonably conclude that the applicant was not in possession of the full breadth of the claimed genus of HLA-E peptide complex specific antibodies at the time the instant application was filed.
Scope of Enablement
Claims 61-72 and 74-99 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 HLA-E-VL9-specific antibodies having fully defined CDRs does not reasonably provide enablement for antibodies having CDRs comprising random, undefined amino acid mutations. 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 or use the invention commensurate in scope with these claims.
The nature of the invention relates antibodies that bind to HLA-E peptide complexes, particularly HLA-E-VL9, in order to prevent the interaction between the complex and inhibitory NKG2A/CD94 heterodimeric receptors expressed on immune cells, including NK cell and CD8+T cell subsets, thereby enhancing NK and CD8+ T cell effector activities (see Technical Field, Page 1 and Background, pages 1-4)
Claim 61 is directed to several antibody clones that bind to HLA-E host peptide complexes, wherein each antibody clone comprises a heavy chain variable (VH) and a light chain variable (VL) region having at least 80% sequence identity to the referenced sequences. As such, the claim encompasses antibodies having random, undefined amino acid mutations, including in the CDR domains.
The specification teaches the isolation and characterization of HLA-E-VL9 peptide complex-specific antibodies derived from the naive IgM B cell BCR repertoire in mice as well as in non-immunized, HCMV seronegative male humans. Several affinity-matured variants of the murine monoclonal antibody (mAb) 34H (3H4 Gvl to 3H4 Gvl2) having mutations at positions 97-100 of the CDR-H3 loop were also generated from an scFv library. The amino acid sequences for the HLA-E-VL9-specific murine and human antibodies, including any respective variants, are disclosed in, e.g. Claim 61 and Figures 8A-8H.
As presently written, claim 61 recites partially defined VH and VL chains of each antibody clone in which at most 20% of the amino acid sequences can vary. Such variation can occur by amino acid substitution, deletion, or insertion and can be made in the CDRs of the antibodies. However, there is no guidance provided in the specification about the type of amino acid mutations that can be made in the VH and/or VL chains of the antibodies –particularly in the CDR sequences – such that the ability of the antibody to bind to HLA-E-VL9 peptide complex is retained. Additionally, there is no evidence demonstrating antibody variants beyond those disclosed in the specification, but encompassed by the claim scope, possess the functional property of binding to the HLA-E-VL9 peptide complex.
It is well-known in the art that amino acid substitutions in the CDR domains of an antibody can negatively impact binding activity (see, e.g. Piche-Nicholas et al, see in particular, Abstract; Colman, see entire document particularly Page 33, Col. 2; and Rudikoff et al, see Abstract). Thus, even a single amino acid substitution at a critical residue can significantly reduce or abolish binding to target antigen. Taken together, the effect of amino acid mutations on antibody binding affinity is not readily predictable. The level of skill and knowledge in the art is such that one of ordinary skill would not be able to readily identify without further testing which amino acid mutations can be made in the VH and VL sequences of the recited antibody clones—particularly in the CDR sequences— such that the ability of the antibodies to bind to target antigen is retained. Claims 62-69, 79, 81-99 incorporate the limitations of claim 61 but do not cure the deficiencies of claim 61 because they still encompass antibody variants having undefined amino acid mutations in the CDR domains that can negatively impact antigen binding. Thus, claims 62-69, 79, and 81-99 are also rejected.
Similarly, claim 70 recites a humanized antibody selected from a group consisting of 3H4, 13F11, 1OC10, 2D6, 3H4 Gv2, 3H4 Gv3, 3H4 Gv4, 3H4 Gv5, 3H4 Gv6, 3H4 Gv7, 3H4 Gv8, 3H4 Gv9, 3H4 Gv1O, 3H4 Gvl 1, 3H4 Gvl2, 3H4hexa, and 3H4sortaNP, wherein each clone comprises VH and VL chains having CDRs that are at least 80% identical to CDRs present in the parent sequence. As presently written, claim 70 thus encompasses antibody variants comprising CDRs in which at most 20% of the amino acid sequences can vary. Such variation can occur by amino acid substitution, deletion, or insertion. However, there is no guidance provided in the specification about the type of amino acid mutations that can be made in the CDR domains such that the ability of the antibody to bind to HLA-E-VL9 peptide complex is retained. Claims 71, 72, 74-78, 80 depend incorporate the limitations of claim 70 but do not cure the deficiencies of claim 70 because they still encompass antibody variants having undefined amino acid mutations in the CDR domains that can negatively impact antigen binding. Thus, claims 71, 72, 74-78, 80 are also rejected.
A person of ordinary skill in the art at the time of filing would have had experience in antibody engineering, including random mutagenesis and screening techniques. Even at this high level of skill, however, the effect of randomly mutating amino acids in the CDR domains—on antigen binding and functional activity cannot be readily predicted without additional testing. In Amgen Inc. v. Sanofi, Aventisub LLC, 987 F.3d 1080 (Fed. Cir. 2021), which the Supreme Court affirmed, the Federal Circuit relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Id. at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement (MPEP 2164.06). Thus, the level of skill does not obviate the need for substantial experimentation across the full scope of the claimed genus to determine which antibody variants retain binding to HLA-E peptide complexes.
Therefore, the specification is not enabling over the full scope of the claims.
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 61-76 and 79-99 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 the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 61 recites “a recombinant antibody or fragment thereof selected from the group consisting of 3H4, CA147, 13F11,10C10, 2D6, CA 18, CA119, CA120, CA122, CA123, CA124, CA125, CA127, CA128, CA129, CA130, CA131, CA132, CA133, CA134, CA135, CA136, CA137, CA138, CA139, CA140, CA141, CA143, CA144, CA145, CA146, CA401, 3H4 Gv2, 3H4 Gv3, 3H4 Gv4, 3H4 Gv5, 3H4 Gv6, 3H4 Gv7, 3H4 Gv8, 3H4 Gv9, 3H4 Gv10, 3H4 Gv11, 3H4 Gv12, CA147hexa, CA147sortaNP, 3H4hexa, and 3H4sortaNP”. An antibody “selected from the group consisting” the recited clones would be expected to be one of the specifically identified clones. If the selected antibody is, for example, 3H4, then its VH and VL amino acid sequences are those of the 3H4 clone itself, not sequences having at least 80% identity to those sequences. However, the claim further recites that each clone comprises a VH and VL chain at least 80% identical to the corresponding VH and VL sequences. It is therefore unclear whether the claim is directed to the specifically recited antibody clones, which inherently possess their defined VH and VL sequences, or instead encompasses antibody variants having VH and VL chains at least 80% identical to those present in the recited clones. Thus, the metes and bounds of patent prosecution desired cannot be reasonably determined. Claims 62-69 and 79-99 incorporate limitations of claim 61 but do not cure the deficiencies of claim 61 and are thus also rejected.
For example claim 63 recites that the recombinant antibody is the clone 3H4 which has fixed VH and VL sequences of SEQ ID NOs: 128 and 129. However, the claim also states that the VH and VL chain of the 3H4 clone is at least 90% identical to the corresponding sequences. If the antibody selected is clone 3H4, it cannot have a variant VH and VL chain. Similarly, claim 68 (which depends on claim 63) further recites that the CDR sequences collectively have no more than 10 amino acid variations as compared to CDRs from the VH and VL sequences of clone 3H4, wherein the framework regions are derived from a human antibody. Clone 3H4 is a murine antibody; thus, it cannot have human framework regions. If the antibody selected in claim 61 is 3H4, then its VH/VL and CDR sequences are those of the 3H4 clone itself, not sequences having amino acid variations to those sequences.
Additionally, the term “most similar” in claim 76 is a relative term which renders the claim indefinite. The term “most similar” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what degree of similarity the VH and VL framework regions possess in relation to the recited sequences.
Claim 70 recites “a humanized antibody or fragment thereof selected from the group consisting of” murine antibody clones including 3H4, 13F11, 1OC10, 2D6, 3H4 Gv2, 3H4 Gv3, 3H4 Gv4, 3H4 Gv5, 3H4 Gv6, 3H4 Gv7, 3H4 Gv8, 3H4 Gv9, 3H4 Gv1O, 3H4 Gv11, 3H4 Gv12, 3H4hexa, and 3H4sortaNP. Humanized antibodies comprise the CDR regions of a non-human antibody (usually murine) with the framework sequences of a human antibody variable domain (see, e.g. Para. 0195 of Specification); however, as presently written, it is unclear whether the recited murine antibody clones define the claimed antibody or merely define the origin of the non-human CDR sequences incorporated into the claimed humanized antibody. Claims 71-76 incorporate limitations of claim 70 but do not cure the deficiencies of claim 70 and are thus also rejected.
For example, claim 75 (which depends on claim 70) recites that the VH comprise framework regions derived from a human antibody wherein the human antibody comprises a VH at least 90% identical to a VH chain present in a murine antibody clone (e.g. SEQ ID NOs: 35-45 and SEQ ID NO: 128). The claim thus encompasses “human” VH chains that are 100% identical to murine VH chains. As such, it is unclear whether the framework regions are obtained from a human or murine VH chain. Similarly, claim 76 recites that the VH and VL chains are “most similar” to the three-dimensional structure of VH and VL chains present in murine antibody clones. Again, it is unclear whether the framework regions of the VH and VL chains are intended to be “most similar” to the 3D structure of murine or human VH and VL chains.
Thus, the metes and bounds of patent protection desired cannot be determined with reasonably certainty.
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 61-64, 79-85, 87-91, 94, 95, and 99 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 10-13, 16-19, 23, 25, 29, 35, 37-39, 44-45, and 47 of copending Application No. 18685192 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims either anticipate or are obvious variants over the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The co-pending claims recite a recombinant monoclonal antibody or antigen binding fragment thereof which binds to an HLA-E-VL9 complex and comprises a VH and VL chain having at least 80% sequence identity to the VH and VL chains listed in Table 1, which includes clones 3H4G_v31, 3H4G_v51, 3H4G_v61, and 3H4G_v62 (co-pending claim 1). the VH chains of clones 3H4 and its variants 3H4 Gv2 -Gv12 recited in the instant claims share at least 90% identity to the VH chain of 3H4G_v31 (SEQ ID NO: 405) (see Sequence Alignments below). The VL chains of clone 3H4 and its variants 3H4 Gv2 -Gv12 (VL of SEQ ID NO: 129) recited in the instant claims share 100% identity to the VL chain of 3H4G_v31 (SEQ ID NO: 409) (see Sequence Alignments below). In some embodiments, the antibody or antigen binding fragment thereof can comprise an Fc moiety or an Fc moiety that has a mutation that reduces binding of the antibody to an Fc receptor and/or increases the half-life of the antibody (co-pending claim 23). In other embodiments, the antibody or antigen-binding fragment thereof is a purified antibody, a single chain antibody, Fab, Fab', F(ab')2, Fv or scFv (co-pending claim 25). Further recited is a nucleic acid molecule comprising a polynucleotide encoding the antibody or antigen-binding fragment thereof (co-pending claim 29). Additionally, the co-pending claims recite an in vitro transcription system to synthesize ribonucleic RNAs encoding the claimed antibodies, comprising: a reaction vessel, a DNA vector template comprising nucleic acid sequence encoding the antibody, and reagents for carrying out an in vitro transcription reaction that produces mRNA encoding an antibody or fragment thereof (co-pending claim 39). The co-pending claims thus encompass vectors comprising the nucleic acid that encodes the antibody as well as RNA that encodes the antibody per instant claims 89-91. Lastly recited is a pharmaceutical composition comprising the antibody or antigen binding fragment thereof, the nucleic acid encoding the antibody or antigen binding fragment thereof and a pharmaceutically acceptable carrier (co-pending claim 35). Per the instant claims, the minimal structure required for an antibody to possess the functional properties recited in instant claims 79-82 is to have a VH and VL chain at least 80% identical to one of the clones listed in the Markush group. As such, the HLA-E-VL9-specific antibodies of the co-pending claims possess the functional properties recited in the instant claims. Additionally, the limitations of instant claims 87 and 88 wherein the antibody is for use as a medicament or for use in the prevention/treatment of a tumor are recitations of intended use that do not alter the structure of the claimed antibody.
Thus, the co-pending claims meet the limitations of instant claims 61-64, 79-85, 87-91, 94, 95, and 99.
VH chain: SEQ ID NO: 128 (instant, clone 3H4) vs SEQ ID NO: 405 (co-pending, clone 3H4G_v31).
PNG
media_image1.png
450
784
media_image1.png
Greyscale
VH chain: SEQ ID NO: 35 (instant, clone 3H4 Gv2) vs SEQ ID NO: 405 (co-pending, clone 3H4G_v31).
PNG
media_image2.png
458
768
media_image2.png
Greyscale
VH chain: SEQ ID NO: 36 (instant, clone 3H4 Gv3) vs SEQ ID NO: 405 (co-pending, clone 3H4G_v31).
PNG
media_image3.png
462
800
media_image3.png
Greyscale
VH chain: SEQ ID NO: 37 (instant, clone 3H4 Gv4) vs SEQ ID NO: 405 (co-pending, clone 3H4G_v31).
PNG
media_image4.png
448
780
media_image4.png
Greyscale
VH chain: SEQ ID NO: 38 (instant, clone 3H4 Gv5) vs SEQ ID NO: 405 (co-pending, clone 3H4G_v31).
PNG
media_image5.png
450
780
media_image5.png
Greyscale
VH chain: SEQ ID NO: 39 (instant, clone 3H4 Gv6) vs SEQ ID NO: 405 (co-pending, clone 3H4G_v31).
PNG
media_image6.png
444
796
media_image6.png
Greyscale
VH chain: SEQ ID NO: 40 (instant, clone 3H4 Gv7) vs SEQ ID NO: 405 (co-pending, clone 3H4G_v31).
PNG
media_image7.png
448
784
media_image7.png
Greyscale
VH chain: SEQ ID NO: 41 (instant, clone 3H4 Gv8) vs SEQ ID NO: 405 (co-pending, clone 3H4G_v31).
PNG
media_image8.png
462
772
media_image8.png
Greyscale
VH chain: SEQ ID NO: 42 (instant, clone 3H4 Gv9) vs SEQ ID NO: 405 (co-pending, clone 3H4G_v31).
PNG
media_image9.png
446
768
media_image9.png
Greyscale
VH chain: SEQ ID NO: 43 (instant, clone 3H4 Gv10) vs SEQ ID NO: 405 (co-pending, clone 3H4G_v31).
PNG
media_image10.png
462
770
media_image10.png
Greyscale
VH chain: SEQ ID NO: 44 (instant, clone 3H4 Gv11) vs SEQ ID NO: 405 (co-pending, clone 3H4G_v31).
PNG
media_image11.png
442
778
media_image11.png
Greyscale
VH chain: SEQ ID NO: 45 (instant, clone 3H4 Gv12) vs SEQ ID NO: 405 (co-pending, clone 3H4G_v31).
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448
786
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Greyscale
Conclusion
No claims are allowable.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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