DETAILED ACTION
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 .
Application Status
The amended claims filed October 30, 2023 are acknowledged. Claims 3, 5-8, 11-12, 14, and 16-20 are amended. Claims 1-21 are pending and under examination herein.
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/PatentLegalFramework), 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:
Specific deficiency - Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). See Figure 1. Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Amended 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 (i.e., “SEQ ID NO:X” or the like) 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.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See page 15, ¶ 0064. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The disclosure is further objected to because recitations of “IgG4-related diseases” throughout should instead recite “IgG4-related disease” (singular). For reference, consider, e.g., Stone (New England Journal of Medicine (2012) 366: 539-551).
Appropriate correction is required.
Drawings
The drawings are objected to because of the following informalities:
The x-axis of Figure 4 does not clearly label all of the specific humanized/affinity-optimized Fv variants that are under comparison in the figure.
The figure legend of Figure 6 appears to contain a typo, specifically “EC5” instead of “EC50” in the label for the [CD20]_H1_L1 variant.
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.
Claim Objections
Claim 19 is objected to because of the following informalities: “IgG4-related diseases” (plural) in line 3 should instead recite “IgG4-related disease” (singular). For reference, consider, e.g., Stone (New England Journal of Medicine (2012) 366: 539-551). In addition, the extra “and” in line 5 before “anti-neutrophil … vasculitides” should be deleted.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claims 1-2, 5-9, and 16-21 are rejected under 35 U.S.C. 103 as being unpatentable over Bernett (US 2016/0355608 A1) in view of United States Food and Drug Administration (Rituxan™ Label (PDF), Webpage: “Rituximab Product Approval Information – Licensing Action”, publicly available on or before May 16, 2016, accessed via Wayback Machine; hereafter “FDA”) and Du (Autoimmunity Highlights (2017) 8: 12).
Bernett discloses heterodimeric antibodies that bind to CD3 and tumor antigens. In one aspect, Bernett provides for an anti-CD20 antibody binding domain comprising VH CDR amino acid sequences of SYNMH, AIYPGNGATSYSQKFQG, and SYYMGGDWYFDV, respectively (which share 100% sequence identity to instant SEQ ID NO: 3, 4, and 5, respectively) and VL CDR amino acid sequences of RASWSVSYIH, ATSNLAS, and QQWTHNPPT, respectively (which share 100% sequence identity to instant SEQ ID NO: 9-11, respectively) (e.g., ¶ 0019-0020), relevant to claim 1. Bernett teaches that in some embodiments, the anti-CD20 antibody binding domains have the C2B8 H1.202_L1.113 (e.g., ¶ 0020). Bernett illustrates an exemplary construct comprising an anti-CD20 heavy chain having SEQ ID NO: 362 (for which residues 1-121 share 100% sequence identity with the instantly claimed VH amino acid sequence of instant SEQ ID NO: 2) and a corresponding light chain having SEQ ID NO: 364 (for which residues 1-106 share 100% sequence identity with the instantly claimed VL amino acid sequence of instant SEQ ID NO: 8 and for which all 213 residues share 100% sequence identity to instant SEQ ID NO: 7) (e.g., Figure 87 on Sheet 120 of 204), relevant to claims 2 and 10.
Further relevant to claim 1, Bernett discloses that there are a number of useful substitutions that can be incorporated into the antibody Fc to confer altered binding to FcγR receptors (e.g., 239D/332E) or increased serum half-life (e.g., 428L/434S) (e.g., ¶ 0305-0306).
Relevant to claims 5-9, Bernett discloses methods of producing a heterodimeric antibody of the invention using host cells, expression vectors, and nucleic acids encoding said antibodies (e.g., ¶ 0024-0025, 0384-0388).
Relevant to claim 16, Bernett discloses pharmaceutical compositions comprising the antibodies of the invention (e.g., ¶ 0391-0396).
Relevant to claims 20-21, Bernett discloses that anti-CD20 compositions of the invention may be used to treat cancers such as non-Hodgkin's lymphoma and chronic lymphocytic leukemia (e.g., ¶ 0389-0390).
However, Bernett does not disclose a monospecific, bivalent anti-CD20 antibody comprising two identical heavy chain polypeptides and two identical light chain polypeptides. Bernett also does not expressly teach using an anti-CD20 antibody of the invention to treat autoimmune disease.
FDA’s Rituxan™ (rituximab) label teaches that rituximab is a genetically engineered chimeric murine/human monoclonal IgG1 kappa immunoglobulin antibody against CD20 composed of two heavy chains (451 amino acids) and two light chains (213 amino acids) (“Description”). Rituximab contains murine light chain and heavy chain variable region sequences and human constant region sequences (“Description”). Based on said description, rituximab is a monospecific, bivalent anti-CD20 antibody. FDA further discloses, “The Fab domain of Rituximab binds to the CD20 antigen on B-lymphocytes and the Fc domain recruits immune effector functions to mediate B-cell lysis in vitro. Possible mechanisms of cell lysis include complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC)” (“Clinical Pharmacology”). FDA discloses that rituximab is indicated for treatment of patients with relapsed or refractory low-grade or follicular, CD20 positive, B-cell non-Hodgkin's lymphoma (“Indications and Usage”). FDA teaches that in clinical studies, patients with relapsed or refractory low-grade or follicular B-cell non-Hodgkin's lymphoma who were administered rituximab experienced an overall 46-48% overall response rate, and disease-related signs and symptoms resolved in 64% of patients who showed said signs and symptoms at study entry (ORR) (“Clinical Studies”).
Du reviews the use of next-generation anti-CD20 monoclonal antibodies in the treatment of autoimmune disease. Du discloses, “Anti-CD20 monoclonal antibodies (mAbs) are used to achieve B cell depletion, and were initially developed to treat B cell proliferative disorders, including non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Anti-CD20 mAbs have subsequently been tested and used in the treatment of the autoimmune disorder rheumatoid arthritis (RA) based on the rationale that the removal of the autoantibody producing or T cell-activating B cells would lead to clinical improvement. The clear clinical benefits of anti-CD20 mAb treatment in RA, particularly in patients refractory to other available treatments, has led to the expansion of anti-CD20 mAbs for other autoimmune diseases with both T cell and B cell etiology, including systemic lupus erythematosus (SLE) and multiple sclerosis (MS)” (Introduction, page 1). See also Table 2 (page 3). Du notes that rituximab, the first anti-CD20 mAb developed as a therapeutic agent, was approved by the FDA for use in treating non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (Introduction, pages 1-2), relevant to claims 17-19. Du discloses that many of the second-generation anti-CD20 antibodies (e.g., the humanized antibodies ocrelizumab, veltuzumab, and Obinutuzumab; the human antibody ofatumumab) have increased binding affinity to Fc receptors and/or increased ADCC to boost their efficacy (e.g., Introduction, page 2; Table 1).
In view of the above, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to generate a monospecific, bivalent anti-CD20 antibody (e.g., having a similar structure to rituximab), wherein the antigen-binding domains comprise a VH having the amino acid sequence of instant SEQ ID NO: 2 (with its respective CDRs) and a VL having an amino acid sequence of instant SEQ ID NO: 8 (with its respective CDRs) and the heavy chain further comprises the amino acid substitutions of 239D, 332E, 428L, and 434S (such as taught by Bernett), and furthermore, to administer such an antibody in the treatment of a cancer or an autoimmune disease. The skilled artisan would have been motivated to do so because Bernett teaches that antibodies comprising said anti-CD20 antigen-binding domain have utility in the treatment of cancer, and FDA and Du further provide that monospecific anti-CD20 antibodies have been successfully used in the treatment of cancer and autoimmune diseases. Based on the teachings of Bernett, one would have been further motivated to incorporate the Fc substitutions of 239D and 332E because these substitutions alter Fc receptor binding and enhance ADCC (which Du notes is a feature that boosts efficacy of the second-generation anti-CD20 therapeutic antibodies) and the substitutions of 428L and 434S because these mutations increase the serum half-life of the therapeutic antibody. There would have been a reasonable expectation of success because (1) known work in one field of endeavor may prompt variations of it for use in the same field based on design incentives if the variations are predictable to those of ordinary skill in the art (e.g., incorporating the anti-CD20 antigen-binding domain taught by Bernett into a monospecific, bivalent antibody format, to be similarly used to treat cancer or an autoimmune disease), and (2) one of ordinary skill in the art would have recognized the utility of the specifically claimed Fc domain substitutions for increasing the efficacy of the therapeutic antibody (i.e., by enhancing ADCC and increasing serum half-life).
Claims 1, 3-4, and 10-15 are rejected under 35 U.S.C. 103 as being unpatentable over Bernett (US 2016/0355608 A1; supra) in view of FDA (Rituxan™ Label (PDF), Webpage: “Rituximab Product Approval Information – Licensing Action”; supra) and Du (Autoimmunity Highlights (2017) 8: 12; supra) as applied to claims 1-2, 5-9, and 16-21 above, and further in view of Lazar (US 2014/0294812 A1).
The teachings of Bernett are described in the 35 U.S.C. § 103 rejection above. As previously noted, Bernett discloses an anti-CD20 light chain having SEQ ID NO: 364 (which shares 100% sequence identity to instant SEQ ID NO: 7, e.g., Figure 87).
However, Bernett does not expressly disclose a monospecific, bivalent anti-CD20 antibody, comprising two heavy chain polypeptides each having the amino acid sequence of instant SEQ ID NO: 1, two light chain polypeptides each having the amino acid sequence of instant SEQ ID NO: 7, wherein the heavy chain constant domain comprises a human IgG1 CH1, a human IgG1 hinge region, and a variant human IgG2 Fc domain, comprising the amino acid sequence of instant SEQ ID NO: 6.
The teachings of FDA and Du are disclosed in the 35 U.S.C. § 103 rejection above.
Lazar discloses Fc domain variants having increased binding to the FcRn receptor and/or increased serum half-life (e.g., Abstract). Lazar notes that the engineered Fc domains of the invention may be adopted in various therapeutic antibodies, including anti-CD20 antibodies (e.g., ¶ 0137-0139). Lazar illustrates an exemplary anti-CD20 heavy chain with enhanced ADCC and an extended half-life (“Hybrid S239D/I332E/M428L/N434S”) with an amino acid sequence of SEQ ID NO: 76 (Figure 81G, sheet 175 of 197), for which residues 122-451 share 100% sequence identity to the constant domain having the amino acid sequence of instant SEQ ID NO: 6, relevant to claims 3-4. See sequence alignment below.
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Lazar shows that the substitution of M428L/N434S in the Fc domain of a hybrid IgG1/IgG2 Fc further increases FcRn binding compared to the effect observed in a wildtype IgG1 or IgG2 constant domain, and improves the on and off kinetic rate constants (i.e., rates of association and dissociation from the antigen) of the antibody compared to wildtype IgG1 Fc. See, e.g., Figures 26A-26B (sheet 46 of 197), Figure 27A (sheet 48 of 197), and Figure 29 (sheet 51 of 197).
Together, the anti-CD20 VH disclosed by Bernett (which shares 100% sequence identity to residues 1-121 of instant SEQ ID NO: 1) and the enhanced hybrid IgG1/2 constant domain disclosed by Lazar (which shares 100% sequence identity to residues 122-451 of instant SEQ ID NO: 1) could be combined to arrive at an anti-CD20 heavy chain comprising the amino acid sequence of instant SEQ ID NO: 1, relevant to claim 10 and its dependent claims.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at a monospecific, bivalent anti-CD20 antibody having a heavy chain amino acid sequence of SEQ ID NO: 1 and a light chain amino acid sequence of SEQ ID NO: 7, wherein the heavy chain constant region comprises the enhanced hybrid IgG1/2 constant region taught by Lazar. The skilled artisan would have been motivated to do so because Lazar teaches that the enhanced hybrid IgG1/2 constant region comprising the amino acid sequence of instant SEQ ID NO: 6 has favorable pharmacokinetic properties compared to wildtype IgG1 or IgG2, in addition to having mutations known to confer enhanced ADCC (239D and 332E) and longer serum half-life (428L and 434S). There would have been a reasonable expectation of success because Lazar discloses that said enhanced hybrid constant regions can be incorporated into the heavy chain of an anti-CD20 antibody construct, and it is prima facie obvious to use a known technique to improve a similar product (i.e., an anti-CD20 antibody) in the same way.
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 1-2, 5-9, and 16-21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,859,011 in view of Bernett (US 2016/0355608 A1; supra), FDA (Rituxan™ Label (PDF), Webpage: “Rituximab Product Approval Information – Licensing Action”; supra), and Du (Autoimmunity Highlights (2017) 8: 12; supra).
Reference patent claim 1 recites a composition comprising an anti-CD20 antigen-binding domain comprising a combination of VH and VL CDRs identical to those recited in instant claim 1.
However, the reference patent claims do not recite a monospecific, bivalent anti-CD20 antibody comprising said combination of CDRs, further comprising a variant Fc domain having the amino acid substitutions of 239D, 332E, 428L, and 434S, numbered according to EU numbering.
The teachings of Bernett, with respect to an anti-CD20 antigen-binding domain comprising identical heavy chain and light chain CDRs, is recited in the 35 U.S.C. § 103 rejection above.
The further teachings of FDA and Du are recited in the 35 U.S.C. § 103 rejection above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to generate a monospecific, bivalent anti-CD20 antibody (e.g., having a similar structure to rituximab), wherein the antigen-binding domains comprise a VH having the amino acid sequence of instant SEQ ID NO: 2 (having the same heavy chain CDRs as those recited in the reference patent) and a VL having an amino acid sequence of instant SEQ ID NO: 8 (having the same light chain CDRs as those recited in the reference patent), and wherein the heavy chain further comprises the amino acid substitutions of 239D, 332E, 428L, and 434S (such as taught by Bernett). The skilled artisan would have been motivated to do so because Bernett teaches that antibodies comprising said anti-CD20 antigen-binding domain have utility in the treatment of cancer, and FDA and Du further provide that monospecific anti-CD20 antibodies have also been successfully used in the treatment of cancer and autoimmune diseases. Based on the teachings of Bernett, one would have been further motivated to incorporate the Fc substitutions of 239D and 332E because these substitutions alter Fc receptor binding and enhance ADCC (which Du notes is a feature that boosts efficacy of the second-generation anti-CD20 therapeutic antibodies) and the substitutions of 428L and 434S because these mutations increase the serum half-life of the therapeutic antibody. There would have been a reasonable expectation of success because (1) known work in one field of endeavor may prompt variations of it for use in the same field based on design incentives if the variations are predictable to those of ordinary skill in the art (e.g., incorporating the anti-CD20 antigen-binding domain taught by Bernett into a monospecific, bivalent antibody format, to be similarly used to treat cancer or an autoimmune disease), and (2) one of ordinary skill in the art would have recognized the utility of the specifically claimed Fc domain substitutions for increasing the efficacy of the therapeutic antibody (i.e., by enhancing ADCC and increasing serum half-life).
Claims 1, 3-4, and 15-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,859,011 in view of Bernett (US 2016/0355608 A1; supra), FDA (Rituxan™ Label (PDF), Webpage: “Rituximab Product Approval Information – Licensing Action”; supra), and Du (Autoimmunity Highlights (2017) 8: 12; supra) as applied to claims 1-2, 5-9, and 16-21 above, further in view of Lazar (US 2014/0294812 A1; supra).
The teachings of the reference patent are recited in the non-statutory double patenting rejection above.
However, the reference patent does not expressly disclose a monospecific, bivalent anti-CD20 antibody, comprising two heavy chain polypeptides each having the amino acid sequence of instant SEQ ID NO: 1 and two light chain polypeptides each having the amino acid sequence of instant SEQ ID NO: 7, wherein the heavy chain constant domain comprises a human IgG1 CH1, a human IgG1 hinge region, and a variant human IgG2 Fc domain, comprising the amino acid sequence of instant SEQ ID NO: 6.
The teachings of Bernett, FDA, Du, and Lazar are disclosed in the 35 U.S.C. § 103 rejections above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at a monospecific, bivalent anti-CD20 antibody having a heavy chain amino acid sequence of SEQ ID NO: 1 and a light chain amino acid sequence of SEQ ID NO: 7 (which comprise identical heavy chain and light chain CDRs, respectively, as disclosed in the reference patent), wherein the heavy chain constant region comprises the enhanced hybrid IgG1/2 constant region taught by Lazar. The skilled artisan would have been motivated to do so because Lazar teaches that the enhanced hybrid IgG1/2 constant region comprising the amino acid sequence of instant SEQ ID NO: 6 has favorable pharmacokinetic properties compared to wildtype IgG1 or IgG2, in addition to having mutations known to confer enhanced ADCC (239D and 332E) and longer serum half-life (428L and 434S). There would have been a reasonable expectation of success because Lazar discloses that said enhanced hybrid constant regions can be incorporated into the heavy chain of an anti-CD20 antibody construct, and it is prima facie obvious to use a known technique to improve a similar product (i.e., an anti-CD20 antibody) in the same way.
Claims 1-2, 5-9, and 16-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 53-57 of co-pending Application No. 19/234,097 in view of Bernett (US 2016/0355608 A1; supra), FDA (Rituxan™ Label (PDF), Webpage: “Rituximab Product Approval Information – Licensing Action”; supra), and Du (Autoimmunity Highlights (2017) 8: 12; supra).
The co-pending reference application recites an anti-CD20 antigen-binding domain comprising an identical combination of heavy chain variable region (VH) and light chain variable region (VL) CDRs as recited in claim 1 (co-pending claim 53). Co-pending claim 54 recites that the anti-CD20 antigen-binding domain comprises a VL having the sequence of “C2B8L1.113” (which shares 100% sequence identity to instant SEQ ID NO: 8) and a VH having the sequence of “C2B8 H1.202” (which shares 100% sequence identity to instant SEQ ID NO: 2). See Figure 87 of Drawings. Co-pending claims 55-57 further recite a nucleic acid composition, expression vector, and host cell encoding said anti-CD20 antigen-binding domain, relevant to claims 5-8.
However, the co-pending reference application does not recite a monospecific, bivalent anti-CD20 antibody comprising said combination of CDRs, further comprising a variant Fc domain having the amino acid substitutions of 239D, 332E, 428L, and 434S, numbered according to EU numbering.
The teachings of Bernett, FDA, and Du are recited in the 35 U.S.C. § 103 rejection above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to generate a monospecific, bivalent anti-CD20 antibody (e.g., having a similar structure to rituximab), wherein the antigen-binding domains comprise a VH having the amino acid sequence of instant SEQ ID NO: 2 and a VL having an amino acid sequence of instant SEQ ID NO: 8, wherein the heavy chain further comprises the amino acid substitutions of 239D, 332E, 428L, and 434S (such as taught by Bernett). The skilled artisan would have been motivated to incorporate into the antibody heavy chain the Fc substitutions of 239D and 332E because these substitutions alter Fc receptor binding and enhance ADCC (which Du notes is a feature that boosts efficacy of the second-generation anti-CD20 therapeutic antibodies) and the substitutions of 428L and 434S because these mutations increase the serum half-life of the therapeutic antibody. There would have been a reasonable expectation of success because (1) known work in one field of endeavor may prompt variations of it for use in the same field based on design incentives if the variations are predictable to those of ordinary skill in the art (e.g., incorporating the anti-CD20 antigen-binding domain described in the co-pending reference application into a monospecific, bivalent antibody format, to be similarly used to treat cancer or an autoimmune disease), and (2) one of ordinary skill in the art would have recognized the utility of the specifically claimed Fc domain substitutions for increasing the efficacy of the therapeutic antibody (i.e., by enhancing ADCC and increasing serum half-life).
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3-4, and 15-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 53-57 of co-pending Application No. 19/234,097 in view of Bernett (US 2016/0355608 A1; supra), FDA (Rituxan™ Label (PDF), Webpage: “Rituximab Product Approval Information – Licensing Action”; supra), and Du (Autoimmunity Highlights (2017) 8: 12; supra) as applied to claims 1-2, 5-9, and 16-21 above, further in view of Lazar (US 2014/0294812 A1; supra).
The teachings of the co-pending reference application are recited in the provisional non-statutory double patenting rejection above.
However, the co-pending reference application does not expressly disclose a monospecific, bivalent anti-CD20 antibody, comprising two heavy chain polypeptides each having the amino acid sequence of instant SEQ ID NO: 1 and two light chain polypeptides each having the amino acid sequence of instant SEQ ID NO: 7, wherein the heavy chain constant domain comprises a human IgG1 CH1, a human IgG1 hinge region, and a variant human IgG2 Fc domain, comprising the amino acid sequence of instant SEQ ID NO: 6.
The teachings of Bernett, FDA, Du, and Lazar are disclosed in the 35 U.S.C. § 103 rejections above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at a monospecific, bivalent anti-CD20 antibody having a heavy chain amino acid sequence of SEQ ID NO: 1 and a light chain amino acid sequence of SEQ ID NO: 7, wherein the heavy chain constant region comprises the enhanced hybrid IgG1/2 constant region taught by Lazar. The skilled artisan would have been motivated to do so because Lazar teaches that the enhanced hybrid IgG1/2 constant region comprising the amino acid sequence of instant SEQ ID NO: 6 has favorable pharmacokinetic properties compared to wildtype IgG1 or IgG2, in addition to having mutations known to confer enhanced ADCC (239D and 332E) and longer serum half-life (428L and 434S). There would have been a reasonable expectation of success because Lazar discloses that said enhanced hybrid constant regions can be incorporated into the heavy chain of an anti-CD20 antibody construct, and it is prima facie obvious to use a known technique to improve a similar product (i.e., an anti-CD20 antibody) in the same way.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Elizabeth A Shupe whose telephone number is (703) 756-1420. The examiner can normally be reached Monday to Friday, 9:00am - 5:30pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643