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 Objections
Claim 3 is objected to because of the following informalities: Claim 3 recites that the anti-IGSF8 antibody comprises VH and VL framework regions corresponding to the recited amino acid sequences or variants having one or more amino acid mutations. The long list of sequences and their respective variants separated only by commas makes it difficult to parse which sequences and variants correspond to a given framework region. For clarity, Applicant is requested to amend the claim to separately delineate the framework region sequences (e.g. by use of semicolons or other punctuation) so that the correspondence is readily apparent. As an example:
“the VH comprises a FR1, FR2, FR3, and/or FR4 comprising the amino acid sequence of QVQLVESGGGVVQPGRSLRLSCAAS (SEQ ID NO: 606) or an amino acid sequence having at most 1, 2, 3, 4, or 5 substitutions, deletions, and/or additions thereof;
MHWVRQAPGKGLEWVAV (SEQ ID NO: 607) or an amino acid sequence having at most 1, 2, 3, 4, or 5 substitutions, deletions and/or additions thereof; …” etc.
Appropriate correction is required.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022,That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, 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 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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 statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Under ST.26, it is impermissible for a SEQ ID number to be used to refer to sequences having fewer than 4 amino acid residues. 37 CFR 831 is reproduced below for Applicant’s convenience (emphasis added by the Examiner).
1.831 Requirements for patent applications filed on or after July 1, 2022, having nucleotide and/or amino acid sequence disclosures.
(a) Patent applications disclosing nucleotide and/or amino acid sequences by enumeration of their residues, as defined in paragraph (b) of this section, must contain, as a separate part of the disclosure, a computer readable Sequence Listing in XML format (a "Sequence Listing XML"). Disclosed nucleotide or amino acid sequences that do not meet the definition in paragraph (b) of this section must not be included in the "Sequence Listing XML." The "Sequence Listing XML" contains the information of the nucleotide and/or amino acid sequences disclosed in the patent application using the symbols and format in accordance with the requirements of §§ 1.832 through 1.834.
(b) Nucleotide and/or amino acid sequences, as used in this section and §§ 1.832 through 1.835, encompass:
(1) An unbranched sequence or linear region of a branched sequence containing 4 or more specifically defined amino acids, wherein the amino acids form a single peptide backbone; or
(2) An unbranched sequence or linear region of a branched sequence of 10 or more specifically defined nucleotides, wherein adjacent nucleotides are joined by:
(i) A 3' to 5' (or 5' to 3') phosphodiester linkage; or
(ii) Any chemical bond that results in an arrangement of adjacent nucleobases that mimics the arrangement of nucleobases in naturally occurring nucleic acids (i.e., nucleotide analogs).
(c) Where the description or claims of a patent application discuss a sequence that is set forth in the "Sequence Listing XML" in accordance with paragraph (a) of this section, reference must be made to the sequence by use of the sequence identifier, preceded by "SEQ ID NO:" or the like in the text of the description or claims, even if the sequence is also embedded in the text of the description or claims of the patent application. Where a sequence is presented in a drawing, reference must be made to the sequence by use of the sequence identifier (§ 1.832(a) ), either in the drawing or in the Brief Description of the Drawings, where the correlation between multiple sequences in the drawing and their sequence identifiers (§ 1.832(a) ) in the Brief Description is clear.
(d) "Enumeration of its residues" means disclosure of a nucleotide or amino acid sequence in a patent application by listing, in order, each residue of the sequence, where the residues are represented in the manner as defined in paragraph 3(c)(i) or (ii) of WIPO Standard ST.26 (incorporated by reference, see § 1.839 ).
(e) "Specifically defined" means any amino acid or nucleotide as defined in paragraph 3(k) of WIPO Standard ST.26.
(f) "Amino acid" includes any D- or L-amino acid or modified amino acid as defined in paragraph 3(a) of WIPO Standard ST.26.
(g) "Modified amino acid" includes any amino acid as described in paragraph 3(e) of WIPO Standard ST.26.
(h) "Nucleotide" includes any nucleotide, nucleotide analog, or modified nucleotide as defined in paragraphs 3(f) and 3(g) of WIPO Standard ST.26.
(i) "Modified nucleotide" includes any nucleotide as described in paragraph 3(f) of WIPO Standard ST.26.
(j) A "Sequence listing XML" must not include any sequences having fewer than 10 specifically defined nucleotides, or fewer than 4 specifically defined amino acids.
[Added 87 FR 30806, May, 20, 2022, effective July 1, 2022]
The XML sequence listing contains no data or is blank (i.e. “000”) for the LCDR2 tripeptide sequence GSP identified by SEQ ID NO: 625 in the claims, Table D, and elsewhere in the Specification. While it is appropriate for the tripeptide to not appear in the sequence listing, per 37 CFR 1.831, it is impermissible for any sequence having fewer than 4 specifically defined amino acids to be defined by SEQ ID NO. As such, Applicant must remove all reference made by way of SEQ ID number for any sequence having fewer than 4 amino acids, including the tripeptide GSP". For example, instant claim 2 must not recite “SEQ ID NO:625” but must instead just spell out the tripeptide “GSP”. Similarly, Table D also cannot assign SEQ ID numbers for any tripeptide sequences. Note that such changes must be made at all occurrences everywhere in the specification, including figures, drawings, and text.
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. In particular, figures 29-36 appear to show CDR sequences on the X-axis of each graph.
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.
Appropriate correction is required.
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.
Claim 16 is 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 enhancing anti-tumor immune responses or enhancing NK cell cytolytic activity in a subject having cancer does not reasonably provide enablement for modulating any generic immune response in any generic subject in need thereof. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The nature of the invention relates to the use of IGSF8 antagonists, particularly anti-IGSF8 antibodies, in the treatment of cancer (see Detailed Description of the Invention on Page 27).
The claim is broadly drawn to a method of modulating an immune response in a subject in need thereof comprising administering a therapeutically effective amount of the anti-IGSF8 monoclonal antibody of claim 1 to the subject.
The specification teaches that several fully human monoclonal antibodies against IGSF8 were generated in silico using a computer-assisted design algorithm based on available sequences from the human B cell receptor (BCR) repertoire. Among the hundreds of sequences obtained, two clones L1 and L2 were selected for further mutagenesis. The L1-23 clone presently claimed is one of the mutants generated having optimized affinity for IGSF8 (Examples 24-25, Table 2, and Table D). Compared to controls, representative L1 and L2 clones enhanced natural kill (NK) and peripheral blood mononuclear cell (PBMC) killing of different cancer cell lines in vitro and slowed tumor growth of B16-F10 melanoma syngeneic mouse model (Examples 29 and 30). While the specification teaches blockade of the IGSF8-KIR3DL2 interaction as a mechanism that enhances NK-mediated killing of tumor cells, the claims broadly encompass modulating an immune response in a subject in need thereof. Immune modulation encompasses a variety of outcomes including enhancement, suppression, or other alteration of immune activity. Further, “a subject in need thereof” is not particularly limited and can potentially encompass cancer patients, infectious disease patients, autoimmune patients, allergy patients, and any other individual for whom immune modulation is desired. The phrase ‘in need thereof’ also implies that the immune modulation is responsive to some need of the subject and therefore has some beneficial effect. However, the specification only provides guidance and examples with respect to enhancement of anti-tumor immune responses but does not demonstrate how the immune modulatory effects of the anti-IGSF8 antibody would be in any way beneficial to non-cancer subjects ‘in need thereof’ as encompassed by the claim.
It is known in the art that NK cell activity can drive autoimmune and inflammatory disease; conversely, under certain circumstances, NK cells can suppress autoimmunity by destroying autoreactive T-cells and B-cells (see, e.g. Zitti et al, Abstract, Sections 4 through 6, and Concluding Remarks). Given this level of unpredictability, evidence demonstrating the enhancement of NK-mediated anti-tumor activity does not reasonably predict whether the immune modulatory effects of the anti-IGSF8 antibody would be beneficial across the full scope of subjects ‘in need thereof’ encompassed by the claim, such as subjects having an autoimmune or inflammatory disorder.
A person of ordinary skill in the art would have knowledge regarding NK cell biology, and antibody therapeutics. However, even at this high level of skill, artisans would not be able to readily predict whether the immune modulatory effects of the anti-IGSF8 antibody would be beneficial in some way to a subject ‘in need thereof’ encompassed by the claims. In the absence of further guidance, artisans would necessarily have to engage in undue trial-and-error experimentation to identify subjects who would benefit from the immune modulation mediated by the claimed anti-IGSF8 antibody.
Therefore, the specification is not enabling over the full scope of the claim.
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 2, 23, 27, and 37 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.
Regarding claim 2, the XML sequence listing contains no data or is blank (i.e. “000”) for the light chain CDR2 tripeptide sequence GSP identified by SEQ ID NO: 625 . Thus, it is unclear to artisans which meaning --- “000” or “DDS”--- should be assigned to SEQ ID NO: 67 as it cannot have both.
Regarding claim 23, the phrase "for example" abbreviated as “e.g.” renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Claim 23 also recites several parenthetical limitations, in particular, “melanoma (including skin cutaneous melanoma)”, “colorectal cancer (including colon cancer)”, “lymphoma (including chronic lymphocytic leukemia and acute myeloid leukemia”, and “uterine cancer (including endometrial carcinoma, uterine carcinoma, uterine corpus endometrial carcinoma)”. It is unclear whether the aforementioned parenthetical text, e.g. “(including colon cancer)” is intended to be a limitation of the term “colorectal cancer”, a mere example of a type of colorectal cancer, or an alternative embodiment. Thus, the metes and bounds of the desired patent protection cannot be determined.
Regarding claim 27, the phrase "such as" occurring multiple times across different groupings renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Thus, the metes and bounds of the desired patent protection cannot be determined.
Regarding claim 37 (which depends on claim 1), there is insufficient antecedent basis for the limitation “antigen-binding portion/fragment thereof” in the claim.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 6 and 27 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 6, depends on claim 1, which recites that the anti-IGSF8 antibody comprises the VH/VL chains and CDRs of clone L1-23, a fully human monoclonal antibody. However, claim 6 recites that the anti-IGSF8 antibody is— in some embodiments—a humanized antibody, a CDR-grafted antibody, or a resurfaced antibody. As noted in the specification, a “humanized antibody” refers to an antibody in which at least one amino acid in a framework region of a non-human variable region (such as mouse, rat, cynomolgus monkey, chicken, etc.) has been replaced with the corresponding amino acid from a human variable region (see page 34). A “CDR-grafted antibody” refers to a humanized antibody in which one or more CDRs of a non-human species has been grafted on the framework regions of a human species (see Page 34). While not defined in the specification, a resurfaced antibody is a non-human monoclonal antibody humanized by changing non-human framework surface residues into those that are typically observed in closely related human counterparts (Desmet et al, Introduction on Pages 341-342). The anti-IGSF8 antibody L1-C3 – a fully human antibody—cannot be a humanized antibody, CDR-grafted antibody, or resurfaced antibody since each of these formats comprises non-human CDRs. Therefore, claim 6 encompass embodiments that fail to incorporate the limitations of claim 1 and otherwise further limit the subject matter of claim 1.
Claim 27, depends on claim 18, which recites that the secondary therapeutic agent is selected from specified categories (e.g. immune checkpoint inhibitor, anti-angiogenesis agent, cancer vaccine) or combinations thereof. As such, a dependent claim should further limit one of these categories. However, claim 27 recites that the second therapeutic agent comprises (a) an antibody or antigen-binding portion thereof effective to treat cancer or (b) an antibody or antigen-binding portion/fragment thereof effective to induce ADCC, ADCP, and/or CDC without indicating that said antibody limits one of the categories recited in claim 18. As such, claim 27 appears to introduce additional classes of secondary therapeutic agents rather than further limiting one of the secondary therapeutic agents recited in claim 18.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. The Examiner suggest canceling the terms ‘humanized antibody’, ‘CDR-grafted antibody’, and ‘resurfaced antibody’ from claim 6.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-6, 8, 9, 16, 17, 18, 23, and 27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-33 of co-pending Application No. 19693922 (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 method of treating cancer in a subject comprising administering an anti-IGSF8 monoclonal antibody comprising the heavy chain CDRs of SEQ ID NOs: 1, 2, 3 (corresponding to SEQ ID NOs: 601, 062, and 605 of the instant claims) and the light chain CDRs of SEQ ID NOs: 4, 5, and 6 (corresponding to SEQ ID NOs: 614, 625, and 631 of the instant claims) (co-pending claim 1) . In other embodiments, the antibody comprises the VH/ VL chain pair of SEQ ID NOs: 7 and 8 (corresponding to SEQ ID NOs: 670 and 694 of the instant claims) (co-pending claim 8). The anti-IGSF8 antibody recited in the co-pending claims is L1-23 (also referred to as mAb-1C2), a LALA-mutated human IgG1 antibody (see Page 12; Table 1 on Page 31-32; and Page 75 of co-pending specification). The L1-23 clone comprises the VH chain fully comprises the framework regions of SEQ ID NOs: 607, 607, 608, and 610 (corresponding to SEQ ID NOs: 606, 607, 608, and 610 of the instant claims); and the VL chain fully comprises the framework regions of SEQ ID NOs: 632, 637, 640, and 642 (corresponding to SEQ ID NOs: 632, 637, 640, and 642 of the instant claims) (see Table 1 on Page 31-32 of co-pending application). Both the co-pending and instant claims recite L1-23 amino acid sequences, and thus the sequences recited in the claims of the co-pending application correspond to sequences recited in the claims of the co-pending application for the L1-23 antibody. The cancer can be a hematological cancer or a solid tumor such as melanoma, cervical cancer, lung cancer, colorectal cancer, endometrial cancer, prostate cancer, pancreatic cancer, head and neck cancer, uterine cancer, liver cancer (co-pending claims 6 and 7). The method further comprises administering one or more additional therapeutic agents comprising an anti-PD-1 antibody (e.g pembrolizumab, nivolumab, or cimiplimab), an anti-PD-L1 antibody (e.g. atezolizumab, avelumab, durvalumab) , an anti-CTLA4 antibody (e.g. ipilimumab or tremelimumab), an anti-LAG3 antibody (e.g. relatilimab), IL-2 (e.g. aldesleukin), or a tumor-infiltrating lymphocyte therapy (e.g. lifleucel) (co-pending claims 18-20). Further recited is a pharmaceutical composition comprising the anti-IGSF8 antibody and a pharmaceutically acceptable solution (co-pending claim 30).
Thus, the co-pending claims meet the limitations of instant claims 1-6, 8, 9, 16, 17, 18, 23, and 27.
Claims 11 and 13-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-33 of co-pending Application No. 19693922, as applied to claims 1-6, 8, 9, 16, 17, 18, 23, and 27 above, and further in view of Reff et al (WO2003048306A2), hereinafter Reff.
The teachings of the co-pending claims have been discussed above and differ from the instantly claimed invention in that a polynucleotide encoding the anti-IGSF8 antibody, a vector comprising the polynucleotide, a host cell comprising the vector, and methods of culturing the host cells under conditions suitable to produce the antibody are not specifically taught.
However, Reff teaches a method of producing functional antibodies in mammalian cells transfected with a polycistronic expression vector, wherein the vector contains the following elements operably linked in the 5' to 3' orientation: a promoter operable in a eukaryotic cell; a DNA sequence encoding at least the variable region of an antibody light chain; an internal ribosome entry site (IRES); and at least one DNA sequence encoding an antibody heavy chain (Abstract). In particular, mammalian or yeast cells containing a polycistronic expression system that expresses antibody light and heavy chain sequences are cultured and functional antibodies are then recovered from the cell culture. The functional antibodies may be produced in batch fed cell cultures at levels suitable for therapeutic use under conditions optimized for maximal commercial output. For example, CHO cells grown in batch fed cultures in which glucose levels are continuously controlled can produce recombinant protein for at least 12 days or more (Para. 0022). The polycistronic expression system disclosed offers an efficient means of producing commercially acceptable amounts of antibodies in recombinant host cell systems, in which a single construct may be utilized for expression of two or more desired protein products, such as the light and heavy chains of a desired antibody (Para. 0016-0017 and Para. 0096).
It would have been obvious to one of ordinary skill in the art to use the recombinant antibody production methods disclosed by Reff, including expression of antibody heavy and light chains from a polycistronic vector in mammalian host cells, to produce the anti-IGSF8 antibody of the co-pending claim. One of ordinary skill in the art would have been motivated to do so since Reff teaches that the polycistronic expression system disclosed therein offers an efficient means of producing commercially acceptable amounts of antibodies in recombinant host cell systems, in which a single construct may be utilized for expression of two or more desired protein products, such as the light and heavy chains of a desired antibody. Therefore, one of ordinary skill in the art would reasonably the anti-IGSF8 antibody of the co-pending claims can be effectively made using the methods disclosed by Reff.
Claims 19 and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-33 of copending Application No. 19693922, as applied to claims 1-6, 8, 9, 16, 17, 18, 23, and 27 above, and further in view of Thomas et al (Thomas, Anish et al. “Antibody-drug conjugates for cancer therapy.” The Lancet. Oncology vol. 17,6 (2016): e254-e262. doi:10.1016/S1470-2045(16)30030-4), hereinafter Thomas.
This is a provisional nonstatutory double patenting rejection.
The teachings of the co-pending claims have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-IGSF8 antibody is conjugated to a cytotoxic agent, such as a toxin.
However, Thomas teaches that an antibody–drug conjugate consists of a monoclonal antibody conjugated to a cytotoxic agent via a linker, wherein the antibody is specific to tumor cell surface proteins, thereby providing the specificity and potency not achievable with traditional drugs. The cytotoxic agent is usually highly potent, with IC50 values in the subnanomolar range in cell culture and can be, for example, an immunotoxin (Abstract, Introduction, and Figure 1 caption).
It would have been obvious to one of ordinary skill in the art to modify the anti-IGSF8 antibody of the co-pending claims such that it is conjugated to a cytotoxic agent such as an immunotoxin. One of ordinary skill in the art would have been motivated to do so in order to enhance the specificity and potency of traditional chemotherapeutic drugs such as immunotoxins in the treatment of cancer as taught by Thomas. Therefore, one of ordinary skill in the art would reasonably expect that an antibody-drug conjugate comprising the anti-IGSF8 antibody of the co-pending claims linked to a cytotoxic agent such as an immunotoxin can effectively treat cancer in a subject.
Claims 1-6, 8, 9, 16, 17, 18, 23, and 27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-33 of copending Application No. 19693869 (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 method of treating cancer in a subject comprising administering an anti-IGSF8 monoclonal antibody comprising the heavy chain CDRs of SEQ ID NOs: 1, 2, 3 (corresponding to SEQ ID NOs: 601, 062, and 605 of the instant claims) and the light chain CDRs of SEQ ID NOs: 4, 5, and 6 (corresponding to SEQ ID NOs: 614, 625, and 631 of the instant claims) (co-pending claim 1) . In other embodiments, the antibody comprises the VH/ VL chain pair of SEQ ID NOs: 7 and 8 (corresponding to SEQ ID NOs: 670 and 694 of the instant claims) (co-pending claim 8). The anti-IGSF8 antibody recited in the co-pending claims is L1-23 (also referred to as mAb-1C2), a LALA-mutated human IgG1 antibody (see Page 12; Table 1 on Page 31-32; and Page 87 of co-pending specification). The L1-23 clone comprises the VH chain fully comprises the framework regions of SEQ ID NOs: 607, 607, 608, and 610 (corresponding to SEQ ID NOs: 606, 607, 608, and 610 of the instant claims); and the VL chain fully comprises the framework regions of SEQ ID NOs: 632, 637, 640, and 642 (corresponding to SEQ ID NOs: 632, 637, 640, and 642 of the instant claims) (see Table 1 on Page 31-32 of co-pending application). Both the co-pending and instant claims recite L1-23 amino acid sequences, and thus the sequences recited in the claims of the co-pending application correspond to sequences recited in the claims of the co-pending application for the L1-23 antibody. The cancer can be a hematological cancer or a solid tumor such as melanoma, cervical cancer, lung cancer, colorectal cancer, endometrial cancer, prostate cancer, pancreatic cancer, head and neck cancer, uterine cancer, liver cancer (co-pending claims 6 and 7). The method further comprises administering one or more additional therapeutic agents comprising an anti-PD-1 antibody (e.g. pembrolizumab, nivolumab, or cimiplimab), an anti-PD-L1 antibody (e.g. atezolizumab, avelumab, durvalumab) , an anti-CTLA4 antibody (e.g. ipilimumab or tremelimumab), an anti-LAG3 antibody (e.g. relatilimab), IL-2 (e.g. aldesleukin), or a tumor-infiltrating lymphocyte therapy (e.g. lifleucel) (co-pending claims 18-20). Further recited is a pharmaceutical composition comprising the anti-IGSF8 antibody and a pharmaceutically acceptable solution (co-pending claim 30).
Thus, the co-pending claims meet the limitations of instant claims 1-6, 8, 9, 16, 17, 18, 23, and 27.
Claims 11 and 13-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-33 of copending Application No. 19693869, as applied to claims 1-6, 8, 9, 16, 17, 18, 23, and 27 above, and further in view of Reff et al (WO2003048306A2), hereinafter Reff.
The teachings of the co-pending claims have been discussed above and differ from the instantly claimed invention in that a polynucleotide encoding the anti-IGSF8 antibody, a vector comprising the polynucleotide, a host cell comprising the vector, and methods of culturing the host cells under conditions suitable to produce the antibody are not specifically taught.
However, Reff teaches a method of producing functional antibodies in mammalian cells transfected with a polycistronic expression vector, wherein the vector contains the following elements operably linked in the 5' to 3' orientation: a promoter operable in a eukaryotic cell; a DNA sequence encoding at least the variable region of an antibody light chain; an internal ribosome entry site (IRES); and at least one DNA sequence encoding an antibody heavy chain (Abstract). In particular, mammalian or yeast cells containing a polycistronic expression system that expresses antibody light and heavy chain sequences are cultured and functional antibodies are then recovered from the cell culture. The functional antibodies may be produced in batch fed cell cultures at levels suitable for therapeutic use under conditions optimized for maximal commercial output. For example, CHO cells grown in batch fed cultures in which glucose levels are continuously controlled can produce recombinant protein for at least 12 days or more (Para. 0022). The polycistronic expression system disclosed offers an efficient means of producing commercially acceptable amounts of antibodies in recombinant host cell systems, in which a single construct may be utilized for expression of two or more desired protein products, such as the light and heavy chains of a desired antibody (Para. 0016-0017 and Para. 0096).
It would have been obvious to one of ordinary skill in the art to use the recombinant antibody production methods disclosed by Reff, including expression of antibody heavy and light chains from a polycistronic vector in mammalian host cells, to produce the anti-IGSF8 antibody of the co-pending claim. One of ordinary skill in the art would have been motivated to do so since Reff teaches that the polycistronic expression system disclosed therein offers an efficient means of producing commercially acceptable amounts of antibodies in recombinant host cell systems, in which a single construct may be utilized for expression of two or more desired protein products, such as the light and heavy chains of a desired antibody. Therefore, one of ordinary skill in the art would reasonably the anti-IGSF8 antibody of the co-pending claims can be effectively made using the methods disclosed by Reff.
Claims 19 and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-33 of copending Application No. 19693869, as applied to claims 1-6, 8, 9, 16, 17, 18, 23, and 27 above, and further in view of Thomas et al (Thomas, Anish et al. “Antibody-drug conjugates for cancer therapy.” The Lancet. Oncology vol. 17,6 (2016): e254-e262. doi:10.1016/S1470-2045(16)30030-4), hereinafter Thomas.
This is a provisional nonstatutory double patenting rejection.
The teachings of the co-pending claims have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-IGSF8 antibody is conjugated to a cytotoxic agent, such as an immunotoxin.
However, Thomas teaches that an antibody–drug conjugate consists of a monoclonal antibody conjugated to a cytotoxic agent via a linker, wherein the antibody is specific to tumor cell surface proteins, thereby providing the specificity and potency not achievable with traditional drugs. The cytotoxic agent is usually highly potent, with IC50 values in the subnanomolar range in cell culture and can be, for example, an immunotoxin (Abstract, Introduction, and Figure 1 caption).
It would have been obvious to one of ordinary skill in the art to modify the anti-IGSF8 antibody of the co-pending claims such that it is conjugated to a cytotoxic agent such as an immunotoxin. One of ordinary skill in the art would have been motivated to do so in order to enhance the specificity and potency of traditional chemotherapeutic drugs such as immunotoxins in the treatment of cancer as taught by Thomas. Therefore, one of ordinary skill in the art would reasonably expect that an antibody-drug conjugate comprising the anti-IGSF8 antibody of the co-pending claims linked to a cytotoxic agent such as an immunotoxin can effectively treat cancer in a subject.
Conclusion
Claim 37 is allowable. No other 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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