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 .
Election/Restrictions
Applicant notes claim 18 was erroneously omitted from PTO-326 form in the previous Office action. This, however, was an obvious typographical error as it was addressed in the Office action as Group II. It is confirmed that claim 18 is pending.
Applicant’s election of Group I and species of Fc variant with loop sequence of SEQ ID NO:47 and additional mutation(s) of L235E_G236N_G237A in the first Fc polypeptide, and mutations G236D_G237F_S239D_S267V_H268D_1332L in the second Fc polypeptide in the reply filed on 12/31/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
As stated by Applicant in the reply (bottom of p. 28), claims 3, 4 (part (b)), 5 (Formula (I), (Ia), (Ib)), 6-8, [and 10] 12 (part (a)), 13, 15, 17, 37, 38, 56-64 and 67 encompass the elected species. The remaining claims are withdrawn from consideration as being drawn to a nonelected invention or species.
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:
A) 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. See Figure 4.
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.
B) Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
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 incorporation-by-reference paragraph, 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.
Drawings
The drawings are objected to under 37 CFR 1.83(a) because they fail to show in Figure 9 the Chain A in green and Chain B in cyan as described in the specification in [0026]. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). 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.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing described as executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Specification
The use of the term R&D Systems ([00608]), GE Healthcare (e.g., [00610]-[00611]) Merck and Thermo Fisher Scientific ([00613]), each of which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Applicant is encouraged to review the specification for occurrences of these and other trade names or marks.
The disclosure is objected to because of the following informalities: The formulas in [00649] and [00651] are not entirely legible. Table 3.1 appears to have mutations that do not coincide with the variant from which the mutations are made. That is, the variants in Table 3.1 have replacement of residues 325-331 with SEQ ID NO:6 (STWFDGGYAT), such that S is residue 325, T is 326, etc.; however, one mutation is set forth as “A327G_A330S_P331S…” and another as “K326D”, wherein the starting amino acids do not appear in the designated positions in SEQ ID NO:6, or at all in the case of K and P.
Appropriate correction is required.
Claim Objections
Claim 37 is objected to because of the following informalities: The claim refers to Tables instead of sequences and/or amino acid substitutions. According to MPEP § 2173.05(s):Reference to Figures or Tables [R-10.2019], “Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).”
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 37 and 38 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 37 is indefinite because it relies on Tables 6.22, 6.24, 6.25 and 6.27, all of which refer to amino acid substitutions and “Strategy”. While these ‘strategies’ are discussed in [00697]-[00698], [00706]-[00707] and [00709]-[00710] these paragraphs refer further to particular Scaffolds. Protocols, Tables and/or Templates, making identification of the sequence of the encompassed heterodimeric Fc variants extremely confusing and difficult at best. Greater transparency/description of variants the claim actually encompasses is needed.
Claim 38 is indefinite for two reasons. First, it lists amino acid substitutions with an asterisk after the number, e.g., D329*I. However, there is no recitation of the significance of the asterisk. While the specification [0027] says an asterisk denotes amino acids within the inserted loop sequence, this is neither consistently used in the specification (e.g., Table 4.5 “A327G”, “A330K” compared to Table 2.5 “D327*D”, “Q330*D”) nor specified in the claim. The asterisk is not an art-recognized symbol for being within an inserted loop. Second, it recites “Template 1” and “Template 7” without setting forth what those are by SEQ ID NO: or other description, making the claim confusing. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Claim Rejections - 35 USC § 112(a)
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.
Claims 3-8, 10, 12, 13, 15-17, 38, 56-64 and 67 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.
Independent claim 3 is drawn to a heterodimeric Fc variant comprising a first polypeptide comprising a replacement of amino acids 325 and 331 with a polypeptide between 8-15 amino acids in length, wherein the variant has increased selectivity of binding to FcγRIIb as compared to a parental Fc region and is a variant of an IgG Fc (numbering according to EU index). The specification states ([0002]) that FcγRIIb “down-regulates immune activity when bound to an antibody Fc. FcγRIIb is the only inhibitory IgG receptor and down-regulates immune activity by inhibiting the activation of B lymphocytes, monocytes, mast cells and basophils induced by activating receptors.” This increased selectivity may be achieved by having a replaced FG loop in the CH2 domain. The specification discloses changes in the same Fc region (FG loop) can give rise to selectivity for two different receptors; however, one skilled in the art must be able to readily envisage which changes will give rise to the desired selectivity, in this case for FcγRIIb. While 20 potential loop templates are disclosed (Table 2.1), only 11 loop templates were shown to be analyzed for FcγRIIb binding (Table 2.2) and had enhanced selectivity for FcγRIIb v. FcγRIIaR compared to the parent (wildtype IgG FG loop). These replacement loops meet the written description provision of 35 USC 112(a) (SEQ ID NO:4-14). Table 6.11 shows longer loops investigated in silico. The longest being 14 amino acids. Even though claim 3 encompasses replacement amino acids 325-331 with 8-15 amino acids, no replacement of 15 amino acids is disclosed. Further, it is reported, “Specifically, in silico modelling indicated that in many cases, the grafted loops formed a hydrophobic anchor that created a cavity. Positions 266, 273 and 325* were identified as the most promising positions to introduce mutations to minimize or remove this cavity.” While variants based on Template 13_3 (13 amino acids long) showed the greatest improvement in FcγRIIb affinity, none of those longer loop variants had significant improvement in selectivity ([00717]). Many of the instant analyses were conducted “in silco”, i.e., by computer simulation and/or computational modeling, which can only present an assumption of results and does not describe actual results. The claims have great breadth, e.g., claims 3, 7, 8, 10, 12, 13, 15, 17 and 56-64 have no limitation related to the sequence of amino acids replacing positions 325-331. Additionally, dependent claims 58-60 require more stringent functional limitations of respectively 1.5-fold increase in FcγRIIb over the parental Fc region, increased relative binding affinity and at least 10-fold increased binding affinity over the parental Fc region. Note that some amino acid substitutions outside the FG loop reduced affinity, so that encompassed Fc variants having a replacement loop may have mutations outside the loop that actually cause a decrease in affinity, as well as effects of their placement in either chain A or chain B (Table 9.1 and, e.g., [00763]-[00764]). The inventors have shown only a limited number of extra-FG loops mutations that either do not affect or that increase affinity.
While Table 2.4 lists loop templates with specific amino acid residue options for particular but not all amino acids within the template, i) the substitutions did not include generically any amino acid but only a limited selection of from 1 to 15 particular amino acids and ii) the substitutions were not at every position, for example, while all had some substitution(s) at position 325 and 326, only template 60 had a substitution at 329 and only templates 231, 168 and 83 had an amino acid immediately after 331 (331*A). While there may be a large number of possible replacement FG loops that may be made in the context of an IgG Fc, Table 2.5 shows only 9 with the required enhanced FcγRIIb selectivity, those derived from 3 templates (1, 19 and 66). While a large number of variants were analyzed for FcγRIIb selectivity enhancement as shown in Tables 2.3 and 2.4, only those in Table 2.5 have data showing actual enhancement. Other mutations outside the FG loop area showed more FcγRIIb selectivity compared to FcγRIIa (Table 3.1). In Example 3,of the top 3 combinations with improved selectivity and/or affinity for FcγRIIb, only one comprised a loop replacement (v19544, Table 3.2). It is important to remember that independent claim 3 requires replacement of amino acids 325-331 of an IgG Fc with more amino acids than the original 7. That means a simple substitution of amino acids of the original 7 does not meet the limitations of the claims, e.g., some variants in Table 4.4 do not provide more than a simple substitution. Further, claim 3 requires an “increased selectivity” and the specification points out that affinity is not the same as selectivity (e.g., Table 6.15 and [00731]), stating for example ([00721]), “Overall, the stability mutation had minimal impact on FcγRIIb binding affinity or selectivity.". It is noted that in Table 2.5, two variants having the same Template mutations (20771 and 20690), only one had increased FcγRIIb selectivity (20771) compared to the control without the loop replacement; although, both had increased selectivity compared to wildtype. It appears that for Template 1 comprising mutations outside the template, most but not all increased or maintained selectivity (Table 3.1). Table 4 shows combinations and variations of loop Templates 1, 7, 66, 151, but all comprised chain A and B mutations outside the template that replaces amino acids 325-331). As discussed in Table 6.6 mutation of G330 with all but Pro increased selectivity compared to Control (Cys not tested). On the contrary, in the case of D329, only D329E and D329G increased selectivity (Table 6.7).
Lesnik et al. (J. Chem. Inf. Model. 60:5475-5486, 7 May 2020) teaches grafting of different antibody FG loops into a wildtype IgG Fc region at that position. While reducing binding to FcγRIIIa was the focus, Lesnik et al. show that substitution of different amino acids at positions in and around the FG loop significantly affect binding. For example, K334A greatly improved the binding to FcγRIIIa (p. 5478, col. 2, second paragraph and Fig. 3). This strongly suggests that it is not merely extending the length of the FG loop as in instant claim 3 but the amino acid content of that variant FG loop that determines FcγRIIIa and FcγRIIb binding selectivity. The skilled artisan would reasonably have expected that the presence of certain amino acids at a position may decrease selectivity of binding and/or affinity to FcγRIIb as compared to a parent Fc region, as has been shown in the instant specification (e.g., Table 4.1A). In one example of Lesnik et al. (p. 5482, col. 1, first full paragraph), an Fc region with a grafted FG loop showed high Fc-silencing, reduction of hydrogen bonds, but with high binding free energy “due to change in the relative positions between CH2 and CH3 domains and between the CH2 and FcγRIIIa and less due to changes within the CH2 domain, which remained relatively stable…(Figure 5F).” This shows it is not sufficient to look only at the CH2 domain where the change occurs, but one must consider how amino acids outside of the FG loop interact with the variant amino acids within the loop and with wildtype amino acids of which the variant loop changes the relative spatial positions. Lesnik et al. presents other examples of FG loop grafting with other sequences that affect the number of hydrogen bonds in the Fc and free energy compared to the wildtype, affecting Fc stability and FcγRIIIa binding (p. 5482, col. 2, through p. 5483, col. 1, second paragraph). As to the FG loop in particular, it is discussed that (p. 5483, col. 2, second paragraph), “The grafted FG loops in the T3 and T4 variants were likely stabilized by the deletions that reduced flexibility and by the conservation of the two rigid prolines, respectively.” Even though Lesnik et al. focused on FcγRIIIa binding, this again points to specific effects of particular amino acids at particular positions. The instant claims encompass any heterodimeric IgG Fc variant comprising replacement of amino acids 325-2331 with any 8-15 amino acids, but there is a functional limitation of having increased selectivity of binding to FcγRIIb as compared to a parental Fc region which also must be met. A representative number and variety of variant Fcs are not disclosed to support the structural breadth of the claims. It does not appear the inventors were in possession of the genus of the heterodimeric Fc variants of the claims.
Further, as to dependent claims 62-64 and especially 67, it is not enough that the polypeptide comprising the heterodimeric Fc variant is fused to one or more antigen-binding domains. The antigen-binding domain(s) must be in such a position as to bind and activate or block the antigen (depending on which leads to antitumor activity). The specification provides as a working example a heterodimeric Fc variant with the binding domain (Fab) of trastuzumab (anti-HER2 antibody), an anti-CD19 and an anti-CD40 full-size antibody scaffold (FSA, e.g., [00742], [00765] and Table 8.2 and 14.1). It was concluded ([00815]) that the results of swapping multiple FSA variants with the different Fabs (anti-HER2, anti-CD19 and anti-CD40) “suggests that the mutations comprised by these variants are transferrable across FSAs and that the Fab comprised by an FSA does not affect the engineered affinity or selectivity.” However, all antibody constructs had the Fab at the N-terminus of the Fc. A further in vivo mouse example used a C5-binding FSA variant that was shown to bind and remove soluble C5 from serum circulation (Example 17). There is no showing it bound to a cell with membrane-bound C5 and resulted in what could represent a therapeutic effect. There is no reasonable expectation that the antigen-binding domain at the C-terminus of the variant Fc domain could function as required, especially for treatment of cancer, including because it is unclear how it would affect Fc activity or lack thereof by, for example, steric hinderance either of the activity of the Fc region or of the antigen-binding region.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
The skilled artisan cannot envision the detailed chemical structure of the encompassed Fc variants having increased selectivity of binding to FcγRIIb as compared to a parental Fc region of a representative number of species covering the broad genus encompassed by the claims, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The product itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
The specification states that variants in Tables 6.22-6.27 had greater FcγRIIb selectivity with respect to (wrt) the Control (i.e., met Criteria A or B); although, the Control is not the wildtype parent Fc ([00728]). Those in Table 2.2 with the exception of template 231 and 168 (SEQ ID NO:4-5) did, as well as those of Table 2.5. A heterodimeric Fc variant comprising these variant Fcs, and for claims 61-46 and 67, wherein the one or more antigen-binding domains is fused to the C-terminus of the Fcs, but not the full breadth of the claim meets the written description provision of 35 U.S.C. § 112(a). Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
N.B., It may be that with clarification for claim 38, e.g., with SEQ ID NO: for the template, it may meet the written description proviso under 35 USC 112(a).
Claim 67 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 wherein the cancer to be treated expresses the TAA or TSA and the antigen-binding domain is at the N-terminus of the Fc region, does not reasonably provide enablement for wherein the cancer does not express the TAA or TSA or wherein the antigen-binding domain is at the C-terminus of the Fc region. 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.
Claim 67 is drawn to a method of treating cancer in a subject in need thereof by administering an effective amount of a polypeptide comprising the heterodimeric Fc variant of claim 3 and one or more tumor-associated antigen (TAA) or a tumor-specific antigen (TSA), wherein the heterodimeric Fc variant of claim 3 comprises a first polypeptide comprising a replacement of amino acids 325 and 331 with a polypeptide between 8-15 amino acids in length and the variant has increased selectivity of binding to FcγRIIb as compared to a parental Fc region and is a variant of an IgG Fc (numbering according to EU index). The specification teaches only 3 TAA or TSA: HER2, CD19 and CD40. HER2 is expressed on some breast cancer cells. CD19 is expressed on malignant B cells (e.g., large B-cell lymphoma). CD40 is expressed on various cancer types, with the main expression in B lymphocytes, dendritic cells (DCs) and monocytes, and its activation induces an antitumor immune response (Zhou et al., Cytokine Growth Factor Rev. 75:40-56, Feb. 2024, and Fig. 1, Sections 4. And 5.) With few exceptions, in order for a cancer to be treated wherein the heterodimeric Fc variant has an antigen-binding domain that binds a TAA or TSA, the cancer cell must express the antigen. As defined by Bourré, L., ((2019) Crown Bioscience. https://blog.crownbio.com/targeting-tumor-associated-antigens-and-tumor-specific-antigens) a TSA is an antigen expressed by tumor cells and a TAA is a self-antigen expressed by tumor cells (see “Key Differences Between TSAs and TAAs). The method of claim 67 has no limitation as to the cancer treated.
Further, it is not enough that the polypeptide comprising the heterodimeric Fc variant is fused to one or more antigen-binding domains. The antigen-binding domain(s) must be in such a position as to bind and activate or block the antigen (depending on which leads to antitumor activity).
The specification provides as working examples trastuzumab (anti-HER2 antibody), an anti-CD19 and an anti-CD40 full-size antibody scaffold (FSA, e.g., [00742], [00765] and Table 8.2 and 14.1). It was concluded ([00815]) that the results of swapping multiple FSA variants with the different Fabs (anti-HER2, anti-CD19 and anti-CD40) “suggests that the mutations comprised by these variants are transferrable across FSAs and that the Fab comprised by an FSA does not affect the engineered affinity or selectivity.” However, all antibody constructs had the Fab at the N-terminus of the Fc. A further in vivo mouse example used a C5-binding FSA variant that was shown to bind and remove soluble C5 from serum circulation. (Example 17) There is no showing it bound to a cell with membrane-bound C5 and resulted in what could represent a therapeutic effect. There is no reasonable expectation that the antigen-binding domain at the C-terminus of the variant Fc domain could function as required for treatment of cancer, including because it is unclear how it would affect Fc activity or lack thereof.
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 3, 7, 8, 10, 12, 13, 15, 56, 57, 61, 62 and 64 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0299296 A1 (‘296) in view of US 2008/0227958 A1 (‘958, cited in the IDS filed 8/1/2024).
US ‘296 relates to Fc region variants in which amino acid alteration(s) in an antibody Fc region enhance FcγRIIb binding and/or selectivity compared to FcγRIIa ([0001]). This is desirable because FcγRIIb is an inhibitory FcγR that has immunosuppressive functions ([0003]). Further, it is the only FcγR expressed on B cells, and its enhanced binding may inhibit B cell activation and suppress IgE production, which could lead to alleviation of arthritis and other autoimmune or inflammatory diseases ([0006]-[0014]). Also ([0020]), “Since FcγRIIa is also expressed on dendritic cells, when antibodies having an Fc with enhanced selective binding to FcγRIIb are used as pharmaceuticals, antigens are not readily presented by dendritic cells and such due to enhanced selective binding to FcγRIIb, and risk of anti-drug antibody production can be relatively decreased. Such antibodies may be useful in that regard as well.” It teaches techniques to promote association of heterologous Fc region variants to promote association between Fc regions containing polypeptides having different amino acids ([0188]-[0189]). It teaches heterodimerized antibodies in which the Fc regions comprise amino acid substitutions produced by methods known in the art ([0192] and [0193]), such as introduction of D356K or K439E in different Fc heavy chains ([0374] described as taught by WO 2006/106905). The antibody comprising the heterodimeric Fc variants also comprised a G236N substitution in both heavy chains ([0375]). Also taught is wherein the antibody had substitution P238D in one chain and G236N in the other, leading to stronger FcγRIIb binding (end of [0376]). An alternative heterodimerizing antibody is taught in which either S239D or S239E was introduced only into one heavy chain ([0377]). Fig. 23 is described as showing ([0454]), “[E]leven alterations enhanced the amount of FcγRIIb binding compared with before introduction when they were further introduced into the P238D variant, but on the contrary, the effect of lowering FcγRIIb binding was observed for eight of those alterations except G237F, G237W, and S239D, when they were introduced into the variant that does not contain P238D (GpH7-B3/GpL16-k0) used in Reference Example 3.” The Fc was from IgG1 ([0422]). Claim 19 teaches a pharmaceutical composition thereof. ‘296 does not teach inclusion of replacement of amino acids 325-331 with a polypeptide 8-15 amino acids long.
US ‘958 teaches IGg1Fc variants having a replacement of Fc amino acids 325-331, the FG loop in CH2, with a peptide with one or more amino acids inserted, including up to 8, wherein the insertion is after amino acid position 329 or 330 [0029]. Also taught is the variant Fc having an increased selectivity for FcγRIIb (e.g., [0137]) and that FcγRIIb-knockout mice showed increased susceptibility to autoimmune disease ([0015]).
It would have been obvious to one of ordinary skill in the art to have an antibody comprising an IgG1 Fc region which had increased binding selectivity to FcγRIIb for the many advantages taught by ‘296 for a therapeutic antibody. It would have been obvious wherein the antibody comprised heterodimeric Fc variant polypeptides to promote association of the two heavy chains, especially if the antigen-binding region of the two heavy chains are not identical. It further would have been obvious wherein the increased binding and/or selectivity to FcγRIIb included a replacement of the FG loop as taught by ‘958 and another substitution such as G236N in one or both chains and/or S239D in one of the heavy chains as taught by ‘296. It would have been obvious wherein the IgG Fc variants were of human IgG1 Fc in order to reduce immunogenicity for the antibody when used therapeutically in a human, e.g., for the treatment of an autoimmune disease, and in a pharmaceutical composition, as suggested by ‘296.
Prior Art
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure.
Armour et al. (2003, cited in the IDS filed 7/11/2024) teaches key amino acids in antibody IgG Fc regions for FcγRIIb and FcγRIIa selectivity, including amino acids 327, 330 and 331 (e.g., Table 1). However, addition of amino acids in that region is not taught.
Escobar-Cabrera et al. (Antibodies 6(7), 16 pages, 2017, p. 10/16, first paragraph) includes two instant inventors as authors and discusses, “Here, we report the first asymmetric designs with reduced effector function and increased thermal stability compared to wild-type CH2 domains (Tables 1 and 2).” “We tested mutations in loops of the CH2 domain, as well as in the lower hinge (Figure 1, Tables 1 and 2). However, the main region we tested includes residues 233–234, which have been shown extensively to be important in mediating effector function [16,17,21].” (p. 10/16, second paragraph) This reference teaches heterodimeric Fc variants comprising symmetric and asymmetric mutations outside the CH2 FG loop and is cumulative to an extent with US 2015/0299296 A1 relied upon above. It does not each replacing the CH2 FG loop with more than 7 amino acids. It does not look specifically at selectivity of binding to FcγRIIb.
Conclusion
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
March 27, 2026
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