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 .
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 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.
Priority
The instant application, filed 06/09/2023, claims domestic benefit to US provisional applications 63/385,877, filed 12/02/2022, and 63/351,282, filed 06/10/2022.
Status of Claims/Application
Applicant’s preliminary amendment of 02/01/2024 is acknowledged. Claims 3, 5, 12, 19-21, 24-25, 27-28, 36, 40-44, 47, 51-56, 59, 63, and 66-67 are amended; claims 57-58, 60-62, 64-65, 68-77, and 79-81 are cancelled; and claim 82 is new.
Claims 1-56, 59, 63, 66-67, 78, and 82 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/07/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
Figs. 7 and 11 recite amino acid sequences without an appropriate SEQ ID NO in either the figure or the specification. It is noted that, for Fig. 11, the specification does provide a SEQ ID NO for Hex-WT, but SEQ ID NOs must also be provided for Hex-2bKQS and Hex-2bKQS.
Instant specification, page 75, [00209] recite the following amino acids that are 4 or more amino acids in length without an appropriate SEQ ID NO: ELLGG and ALPAPIE.
Instant specification, page 84, [00222] recites the amino acid sequence “LALAPG” without an appropriate SEQ ID NO.
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the 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.
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.
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification Objection
The use of the term “NANOBODY™”, 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.
The instant specification recites “nanobody” on page 7 in the fourth line from the bottom of [0011]). The term “NANOBODY” is a trademark and should be capitalized anywhere that it appears and/or include an appropriate symbol, such as ™. The term should also be accompanied by generic terminology.
Duplicate Claim Warning
Applicant is advised that should claims 19 and 20 be found allowable, claims 51 and 52 will be objected to under 37 CFR 1.75 as being a substantial duplicates thereof, respectively. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
In this case, both claims 19 and 51 depend on claim 1 and limit the polypeptide comprising a mutant or variant human IgG Fc domain thereof as being aglycosylated. Similarly, both 20 and 52 depend on claim 1 and limit the polypeptide to being glycosylated. As such, claims 19 and 51, and 20 and 52 are the same in scope and are duplicates of each other.
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 1-56, 59, 63, 66-67, 78, and 82 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.
Claims 1-9, 11-13, 15, 17, 25-27, 40, and 43-44 are drawn to a polypeptide comprising a mutant or variant human IgG Fc domain capable of binding FcγRIIb, where the mutant or variant human IgG Fc domain comprises the recited substitution mutations with amino acid position numbering according to the Kabat system. However, there is insufficient antecedent basis for the recited positions as the claim(s) do not recite a parent sequence to which the positions recited could be referring to, rendering the metes and bounds of the claim indefinite.
Appropriate correction is required.
Claims 10, 14, 16, 18-24, 28-39, 41-42, 45-56, 59, 63, 66-67, 78, and 82 are rejected by virtue of their dependency on a rejected claim as they do not resolve the ambiguity discussed above.
In the instant office action, the claims are interpreted as referencing the wild-type Fc of instant SEQ ID NO: 1.
Claims 1-9, 11-13, 15, 17, and 26, recite substitution mutations using the following format (example from claim 1): “valine at position 233 (E233V)” The recitation prior to the parentheticals includes the amino acid that is substituted into the recited position. The recitation within the parentheticals includes the amino acid that is currently in the recited position (in this example “E” for glutamic acid), the position (233), and the amino acid that is substituted into the position (V). As discussed above, the claims do not recite a parent sequence to which the substitutions are made and; therefore, the limitations within the parentheticals are narrower embodiments of the preceding limitation as they require a specific amino acid to be in the recited position prior to substitution. As the limitations within the parentheticals are narrower embodiments of the preceding limitations, the claims are indefinite as it is unclear if the limitations are limiting features of the claimed invention or exemplary embodiments, rendering the metes and bounds of the claims indefinite.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). For example, claim 1 recites the broad recitation “valine at position 233, and the claim also recites “E233V” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Appropriate correction is required.
Claim 10, 14, 16-25, 27-56, 59, 63, 66-67, 78, and 82 are rejected by virtue of their dependency on a rejected claim as they do not resolve the ambiguity discussed above.
Claim 1 recites “proline at position 238 (H268P)” in lines 4-5. It is unclear what position is claimed for the proline substitution as the position of the mutation inside of the parenthesis does not match the position immediately prior, rendering the metes and bounds of the claim indefinite.
Appropriate correction is required.
Claims 1-56, 59, 63, 66-67, 78, and 82 are rejected by virtue of their dependency on claim 1, as they do not resolve the ambiguity discussed above.
In the instant office action, the claim is interpreted as requiring a H268P substitution based on the modifications that are in Fc V8.2 (SEQ ID NO: 2), 2b18K (SEQ ID NO: 3), 2b18KQ (SEQ ID NO: 4), and 2b18KQS (SEQ ID NO: 5) (see instant specification, Table 4).
Claim 8 recites “aspartic acid at position 237 (S267D)” in line 2. It is unclear what position is claimed for the aspartic acid substitution as the position of the mutation inside of the parenthesis does not match the position immediately prior, rendering the metes and bounds of the claim indefinite.
Appropriate correction is required.
Claims 9 and 10 are rejected by virtue of their dependency on claim 8, as they do not resolve the ambiguity discussed above.
In the instant office action, the claim is interpreted as requiring a S267D substitution based on the modifications that are in Fc V8.2 (SEQ ID NO: 2) (see instant specification, Table 4).
Regarding claims 53-55, the term “essentially no” in claims 53-55 is a relative term which renders the claim indefinite. The term “essentially no” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In this case, the claims limit the Fc domain by the functional limitations that the domain triggers no or “essentially no” antibody mediated phagocytosis, cell cytotoxicity, or induction of activating FcγR. The instant specification does not provide a definition of “essentially no” and; therefore, the metes and bounds of the claims are indefinite.
Appropriate correction is required.
Claim 47 recites the limitation "the polypeptide or antibody" in lines 1-2. There is insufficient antecedent basis for “the antibody” in the claim. Claim 47 depends on claim 1, which does not recite an antibody.
Appropriate correction is required.
Claim 63 depends on cancelled claim 60, rendering the metes and bounds of the claim indefinite. In the instant office action, the claim is interpreted as being dependent on claim 59.
Claim 50 contains the trademark/trade name “NANOBODY™”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a particular product and, accordingly, the identification/description is indefinite.
Claim Rejections - 35 USC § 112(a)- Written Description
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 21-24 and 53-55 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.
The instant claims depend on claim 1 and further limit the polypeptide of claim 1 by the recited functional limitations. Specifically, claims 21-23 recite what the Fc domain of claim 1 does not selectively or detectably bind to and claim 24 recites a fold- degree to which domain has reduced binding to FcγRIIaR131 compared to the wide type Fc binding. Claims 53-55 recite functional limitations in which the polypeptide of claim 1 is limited to those that trigger no, or essentially no, antibody mediated phagocytosis, cell cytotoxicity, and induction of activating FcγR.
Claim 1, on which claims 21-24 and 53-55 depend, is drawn to a polypeptide comprising a mutant or variant human IgG Fc domain that is capable of binding to human FcγRIIb, wherein the Fc domain comprises substitution mutations of E223V, S239L, H268P, A327L, L328A, and substitutions in positions L234 and L235. As such, claim 1 is drawn to a genus of polypeptides which encompasses any parent human IgG Fc domain with the recited mutations. Additionally, the claim uses “comprising” language with regards to the mutations that are recited. In the absence of a limiting definition for “comprising” by applicant in the instant disclosure, the transitional phrase “comprising” is interpreted per MPEP 2111.03, which states that “The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.” Therefore, based on the use of “comprising” the claim encompasses Fc variants with the recited amino acid substitutions in addition to any other unrecited substitution.
Claims 21-24 and 53-55, which recite functional limitations, claim the polypeptide by what it does rather than what it is. While claim 1 does provide some structure to the polypeptide, there is no indication that the structure recited would perform the claimed function over the entire genus encompassed by claim 1. Specifically, the instant disclosure does not provide a representative number of species of the instantly claimed Fc variant performing the claimed function, nor does the disclosure identify a structure function relationship that would allow for the predictable identification of which Fc variants encompassed by claim 1 would be capable of performing the claimed function.
The examples of the disclosure detail a library construction strategy for the isolation of IgG1 Fc domains that bind to FcγRIIB (page 75, Example 1). A list of Fc variants that were identified and used in further experiments is shown in Table 4 (pages 76-77), which is duplicated below for convenience.
PNG
media_image1.png
319
645
media_image1.png
Greyscale
The disclosure identifies EF, V12, and V11 as Fc variants that were already known in the prior art while V8.2, 2b18K, 2b18KQ, and 2b18KQS are the Fc variants of the instant invention (page 76, [00210]). It is also noted that the disclosure identifies V8.2 as instant SEQ ID NO: 2; 2b18K as SEQ ID NO: 3; 2b18KQ as SEQ ID NO: 4; and 2b18KQS as SEQ ID NO: 5. These sequences represent the species of the claimed invention that applicant was in possession of at the time of the effective filing date.
The examples disclose that, to verify the binding affinity to Fcγ receptors, biolayer interferometry assays were performed. Results are shown in Table 5 (pages 78-79), which is duplicated below for convenience.
PNG
media_image2.png
296
682
media_image2.png
Greyscale
With regards to the functional limitation recited in claim 22, specifically that the polypeptide does not selectively or detectably bind to human FcγRI, Fc variants 2b18K and 2b18KQS are the Fc variants of the instant disclosure that are demonstrated as having the instantly claimed function. V8.2 and 2b18KQS, however, were not assayed and; therefore it is unclear if these variants are species of the invention claimed in claim 22.
Similarly, with regards to the function recited in claim 23, in which the Fc domain is claimed to not selectively or detectably bind to any of human FcγRIIa H131, FcγRIIIa F158, and FcγRIIIa V158, only variants V8.2, 2b18K, and 2b18KQS are shown to have the recited function and are species of the instantly claimed invention.
With regards to the fold change in binding to FcγRIIa R131 that is recited in instant claim 24, it appears that only 2b18KQS was tested for binding affinity (pages 80-81; Table 6). The disclosure states that the variant showed almost non-detectable binding to FcγRIIa R131, which is a 40-fold decrease compared to wild type Fc (page 82, [00214]). Therefore, 2b18KQS is the only variant that is demonstrated in the instant disclosure as having the function recited in instant claim 24.
The disclosure further studied phagocytosis with the Fc variants (page 83, Example 4). The example discloses that FHP-1 cells expressing FcγRIIa H131 were used, to which 2b18K, 2b18KQ, and 2b18KQS did not detectably bind. The 2b18K, 2b18KQ, and 2b18KQS variants were tested with LALAPG coated beads as a negative control. The disclosure states that no FcγR mediated phagocytosis was detected among the Fc variant domains, which was consistent with the binding assay results (page 84, [00222]). The results are shown in Fig. 4, and demonstrate that variants 2b18K, 2b18KQ, and 2b18KQS perform the function recited in instant claim 53.
The disclosure also states that 2b18K, 2b18KQ, and 2b18KQS did not induce the activating FcγR and trigger effector functions, the results of which are shown in Fig. 6. Demonstrating that variants 2b18K, 2b18KQ, and 2b18KQS are capable of performing the function recited in instant claim 55.
The disclosure further studied complement or activating effector functions using 2b18K, 2b18KQ, and 2b18KQS variants and states that no complement or activating FcγR mediated effector functions were detected (page 84, [00226]). Results which demonstrate that variants 2b18K, 2b18KQ, and 2b18KQS are capable of performing the function recited in instant claim 54.
The variants V8.2, 2b18K, 2b18KQ, and 2b18KQS, only some of which are demonstrated in the instant disclosure as having the claimed functions, are not a representative number of species of the entire scope of the claimed genus. The disclosure also does not provide a structure function correlation that would allow for the predictable identification of which variants would be capable of performing the claimed functions.
The prior art also does not provide a representative number of species performing the claimed function nor does the prior art provide a structure function relationship that would allow for the predictable identification of which species would perform the claimed function. Rather, the art suggests that the function of Fc variants is a result of the structure of the entire Fc domain.
For instance, Mimoto, F., et al (2013) Engineered antibody Fc variant with selectively enhanced FcγRIIb binding over both FcγRIIa R131 and FcγRIIa H131 Protein engineering, design, & selection 26(10); 589-598 teaches that engaging Fc inhibitory FcγRIIb by Fc region has been recently reported to be an attractive approach for improving the efficacy of antibody therapeutics (abstract). In order to exploit known properties, engineering Fc region to increase the binding affinity to FcγRIIb is considered to be a promising approach. Introducing S267E/L328F substitutions into the Fc region of human IgG1 increased the binding affinity to FcγRIIb 430-fold, without increasing that to FcγRI, FcγRIIa H131, or FcγRIIIa. However, it was reported that S267E/L328F also enhanced the binding to one of the FcγRIIa allotypes, FcγRIIa R131, to a level similar to the binding of FcγRIIb. Therefore, when applying substitutions to mAb therapeutics, the consequence of increasing the binding to FcγRIIa should be considered (paragraph bridging pages 589-590). Mimoto also teaches that FcγRIIb and FcγRIIa R131 are structurally similar (abstract).
Mimoto investigated antibodies with selectively enhanced binding to FcγRIIb over both FcγRIIa R131 and FcγRIIa H131. In order to identify an antibody, Mimoto screened a large set of single substituted variants of human IgG1 for binding to human FcγR and found a distinct variant that distinguishes FcγRIIb from both FcγRIIa allotypes. Its crystal structure was studied in complex with human FcγRIIb which elucidated the structural recognition mechanism by which it recognizes FcγRIIb over both FcγRIIa allotypes. In order to improve FcγRIIb binding, the variant was further optimized (page 590, left column, paragraph 3).
The teachings of Mimoto suggest that the binding affinity of Fc variants is not predictable based on structure alone. For instance, Mimoto teaches a previously used mutant that bound FcγRIIb and FcγRIIa R131 and states that it is because they are structurally similar. Additionally, in order to identify an antibody that bound to FcγRIIb over both FcγRIIa R131 and FcγRIIa H131, Mimoto applied a comprehensive mutagenesis and structure-guided design based on crystal structures indicating that structure-function was not predictable and required significant testing and analysis.
Bartsch, Y.C., et al (2025) Combinatorial Fc modifications for complementary antibody functionality MABS 17(1); 2465391; 1-10 demonstrates that, even several years after the effective filing date of the claimed invention, Fc variant structure-function was not predictable. Bartsch teaches that In addition to binding and neutralizing activity, antibodies, via the crystallizable fragment (Fc), can leverage Fc receptors on innate effector cells leading to the recruitment of phagocytes, NK cells, or deposition of complement; all functions that might be equally important for elimination of malignant or infected cells. Importantly, Fc-mediated activity can be precisely controlled by protein engineering as a versatile tool to improve biological activity. Such Fc modifications; however, are usually designed to enhance specific Fc-mediated functionalities by enhancing binding to dedicated Fc receptors (page 1, Introduction). To determine whether pairs of mAbs with different Fc modifications can be combined for functional complementarity, Bartsch investigated in vitro activity of two mAb libraries, each equipped with 60 engineered Fc variants. While some combinations of Fc variants displayed additive functional effects, others were detrimental, suggesting that the functional outcome of Fc mutations is not easily predicted (abstract). Bartsch concludes that careful selection of combinatorial Fc modifications to fine tune their activity and tailor it to the therapeutic goals will be critical and future studies will need to determine ideal Fc modifications for optimal efficacy in vivo (page 7, left column, paragraph 1).
The teachings of Bartsch further demonstrate unpredictability in combined Fc modifications as some can be additive while others can be detrimental. Results which suggest that it is the specific amino acid sequence of the Fc variant that imparts enhanced properties, such as those claimed.
As discussed above, neither the instant disclosure nor the prior art provide a representative number of species of the claimed genus performing the functions claimed in instant claims 21-24 and 53-55. Additionally, the disclosure and prior art do not provide a structure-function relationship that would allow for the predictable identification of which Fc variants encompassed by the claimed genus would be capable of performing the claimed functions. Therefore, the claims were found not to meet the written description requirements of 35 USC 112(a).
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.
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.
Claims 1, 3-9, 11-13, 19-20, 25-31, 33-36, 47-52, 56, 59, 63, 66-67, 78, and 82 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0315284 A1 (Lazar, G.A., et al) 05 Nov 2015.
US’284 teaches optimized Fc variants, engineering methods for their generation, and their application, particularly for therapeutic purposes (page 1, [0002]).
The Fc region of an antibody interacts with a number of Fc receptors and ligands, imparting an array of important functional capabilities referred to as effector functions. For IgG, the Fc region, as shown in Fig. 1, comprises Ig domains Cγ2 and Cγ3 and the N-terminal hinge leading to Cγ2. An important family of Fc receptors for the IgG class are the Fc gamma receptors (FcγRs). These receptors mediate communication between antibodies and the cellular arm of the immune system. In humans, this family includes FcγRI (CD64), including isoforms FcγRIa, FcγRIb, and FcγRIc; FcγRII (CD32), including isoforms FcγRIIa (including allotypes H131 and R131), FcγIIb (including FcγRIIb-1 and FcγRIIb-2), and FcγRIIc; and FcγRIII (CD16), including isoforms FcγRIIIa (including allotypes V158 and F158) and FcγRIIIb (including allotypes FcγRIIIb-NA1 and FcγRIIIb-NA2). These receptors typically have an extracellular domain that mediates binding to Fc, a membrane spanning region, and an intracellular domain that may mediate some signaling event within the cell (page 1, [0005]).
US’284 teaches Fc variants that are optimized for a number of therapeutically relevant properties. These Fc variants are generally contained within a variant protein, that preferably comprises an antibody or an Fc fusion protein (page 4, [0019]). The Fc variants, and proteins containing these variants, have at least 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 or more amino acid substitutions compared to the parent Fc polypeptide, for example, the Fc region of SEQ ID NO: 1. The Fc variants exhibit altered Fc ligand binding compared to the parent Fc (page 5, [0021]-[0022]).
US’284, SEQ ID NO: 1 comprises the wild-type Fc parent sequence (instant SEQ ID NO: 1) of the instant application as shown in the ABSS alignment below:
PNG
media_image3.png
365
736
media_image3.png
Greyscale
US’284 teaches that the Fc variants comprise at least one amino acid substitution at a position selected from the group consisting of 221, 222, 223, 224, 225, 227, 228, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 243, 244, 245, 246, 247, 249, 255, 258, 260, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 278, 280, 281, 282, 283, 284, 285, 286, 288, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 313, 317, 318, 320, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, and 337, wherein the numbering of the residues in the Fe region is that of the EU index as in Kabat (page 4, [0020]). Positions which comprise the position of the substitutions of the instant claims.
US’284 further teaches preferred Fc substitutions in these positions including E333V, S239L, H268P, A327L, L328A, L234, and L235 (pages 4-5, [0020]).
US’284 also teaches the preferred Fc substitutions of T299A, L234P or L234D, L235T or L235F, S267D, I332Q, G236R, G237D, A330H, E333I, and T299L (pages 4-5, [0020]). The IgG Fc region disclosed by US’284 also comprises a serine at position 298 and a threonine at position 299 (SEQ ID NO: 1; pages 4-5, [0020]).
US’284 constructed Fc variants, with each of these substitutions at least individually, and experimentally tested them. Figures 41a-41pp provides the binding data of the variants (page 11, [0077]). US’284 demonstrates that, Fc regions with each of the modifications above were capable of binding to human FcγRIIb.
US’284 further teaches that the Fc domains are aglycosylated or glycosylated (page 7, [0031]; Figure 39).
US’284 further teaches that the modified Fc region is part of an antibody or a Fc fusion (page 3, [0010]). US’284 teaches that the “antibody” is a protein consisting of one or more polypeptides substantially encoded by all or part of the recognized immunoglobulin genes. The term includes full length antibodies and antibody fragment, and may refer to a natural antibody from any organism, an engineered antibody, or an antibody generated recombinantly for experimental, therapeutic, or other purposes as defined. The term “antibody” includes antibody fragments known in the art, including scFv. US’284 further teaches that the antibody can be agonistic (page 11, [0083]). US’284 further teaches that full length antibodies include variable and constant regions. For example, in most mammals, including humans and mice, the full length antibody of the IgG class is a tetramer and consists of two identical pairs of two immunoglobulin chains, each pair having one light and one heavy chain, with each light chain comprising immunoglobulin domains VL (variable light chain domain) and CL (constant light chain domain) and each heavy chain comprising a VH (variable heavy chain domain) and constant regions. In some mammals, for example in camels and llamas, IgG antibodies may consist of only two heavy chains, each heavy chain comprising a variable domain attached to the Fc region (page 11, [0085]), which are single domain antibodies.
US’284 further teaches that virtually any antigen may be targeted by the Fc variants, and provides numerous examples, including CD40, that are non-FcR receptors (page 16, [0113]). US’284 also teaches that the target of the antibody can be soluble or cell surface bound (page 18, [0115]).
US’284 further teaches that the fusion and conjugate partners are Fc polypeptides and that the Fc variant may be a multimeric Fc polypeptide, comprising two or more Fc regions. The advantage of such a molecule is that it provides multiple building sites for Fc receptors with a single protein molecule (page 29, [0169]). US’284 teaches the use of the Fc regions in an oligomer, including a homo- or hetero-oligomer (pages 15-16, [01110]).
US’284 further teaches that effector function can be a problem for radiolabeled antibodies and antibodies conjugated to toxins, referred to as immunotoxins. These drugs can be used to destroy cancer cells, but the recruitment of immune cells via Fc interaction with FcγRs brings healthy immune cells in proximity to the deadly payload, resulting in depletion of normal lymphoid tissue along with targeted cancer cells. This problem can potentially be circumvented by using IgG isotypes that poorly recruit complement or effector cells. An alternative solution is to develop Fc variants that reduce or ablate binding (page 13, [0102]). The Fc variants disclosed may be fused or conjugated to one or more other molecules or polypeptides. Conjugate and fusion partners may be any molecule, including small chemical compounds and polypeptides, including toxins (page 28, [0164]). US’284 further teaches methods of covalently linking the Fc variants to conjugate partners (page 30, [0171]).
US’284 further teaches that the amino acid substitutions are made by generating a nucleic acid that encodes the variant (page 69, claim 28). US’284 teaches a method of making the polypeptide comprising culturing a host cell under conditions where the polypeptide is produced, then purifying said polypeptide (page 69, claim 29).
US’284 further teaches pharmaceutical compositions comprising the Fc variants and physiologically or pharmaceutically acceptable carrier or diluent (page 7, [0035]; page 37, [0210]). US’284 teaches that it is also possible to administer a nucleic acid encoding the Fc variant, for example, by retroviral infection, direct injection, or coating with lipids, cell surface receptors, or other transfection agents (page 38, [0218]).
US’284 further teaches a method of treating a patient in need thereof, said method comprising administering a polypeptide produced according to the methods disclosed (page 69, claim 40). A “patient” includes both humans and other animals, preferably mammals, and can include both human therapy and veterinary applications. The term “treatment” is meant to include therapeutic treatment, as well as prophylactic or suppressive measures for a disease or disorder. For example, successful administration of an Fc variant results in treatment of the disease (page 36, [0202]). As US’284 teaches methods of administering the Fc variants in the form of an antibody to a mammalian subject, US’284 teaches methods of binding proteins in mammalian subjects.
While US’284 does not exemplify the claimed combination of substitution mutations, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to make the claimed substitutions based on the teachings of US’284. It would have been obvious to make these substitutions as US’284 teaches methods of optimizing Fc domains for therapeutic purposes and provides Fc positions at which amino acid modifications can be made to generate optimized Fc variants, including the positions and substitutions of the instantly claimed invention. Additionally, US’284 made Fc variants and experimentally tested binding and provides data on each substitution allowing for modification with a reasonable expectation that the Fc domain will be capable of binding human FcγRIIb, as claimed.
Claims 2, 14, 21-24, 28-32, and 53-55 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0315284 A1 (Lazar, G.A., et al) 05 Nov 2015 as applied to claim 1 above, and in further view of US 2016/0376371 A1 (Ravetch, J., et al) 29 Dec 2016.
US’284 teaches the polypeptide of claim 1 as discussed in detail above.
US’284, however, does not disclose that the Fc domain further comprises a S298 substitution. US’284 also does not explicitly disclose that the antibody is an anti-CD40 agonistic antibody.
US’371 teaches agonistic antibodies, or antigen binding portions thereof, that bind human CD40. Such antibodies optionally comprise Fc regions with enhance specificity for FcγRIIb. US’371 further provides methods of treatment of cancer or chronic infection by administering the antibodies to a subject in need thereof (abstract). US’371 teaches that the antibodies have constant domains with modified Fc regions having enhanced affinity for FcγRIIb as compared with their affinity for other Fc receptors, i.e., activating receptors. Such agonistic anti-CD40 antibodies with enhanced FcγRIIb specificity are expected to exhibit superior efficacy in treatment of cancer and chronic infection. US’371 teaches that such FcγRIIb-specific agonistic anti-CD40 mAbs may exhibit enhanced adjuvant effects by increasing the maturation of dendritic cell promoting expansion and activation of cytotoxic CD8+ T cells, leading to enhanced anti-tumor response. US’371 considers that FcR-mediated signal enhancement of agonistic CD40 antibodies could be due to increased receptor clustering, or crosslinking, of the antibodies contributing to therapeutic efficacy. Cross-linking of CD40 agonistic antibodies by FcR engagement by the Fc portion of the antibody may increase signal strength and thereby enhance activation of the cells (pages 35-36, [0298]).
US’371 teaches that mutations can be introduced to antibodies to restore effector function, for instance to aglycosylated antibodies. US’371 teaches that mutations that can restore FcγR binding include S298G and/or T299 A/G/ or H (page 17, [0142]).
US’371 further teaches full-length antibodies comprising VH and VL domains (page 18, [0152]-[0154]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the mutant Fc domain disclosed by US’284 to further include a S298G mutation and to have the antibody be a full-length anti-CD40 agonistic antibody as taught by US’371. An ordinarily skilled artisan would have been motivated to further include the S298G mutation as US’371 teaches that such mutation, in combination with T299A, can restore effector function, increase signal strength, and the activation of cells in an agonistic antibody. It would have been obvious to have the antibody be a full-length anti-CD40 agonistic antibody as US’371 teaches that such antibodies can comprise mutated Fc regions and be used in the treatment of diseases including cancer and chronic infection. An ordinarily skilled artisan would have had a reasonable expectation of success as US’284 teaches the mutation T299A, which US’371 teaches the S298G mutation in combination with. Additionally, US’284 teaches that the antibody can be agonistic and also that the target can be CD40 demonstrating a nexus among the art.
Regarding claim 14, as discussed above, US’284 teaches the parent human IgG Fc domain SEQ ID NO: 1. US’284, SEQ ID NO: 1 has the following alignment with instant SEQ ID NO: 3:
PNG
media_image4.png
287
582
media_image4.png
Greyscale
As discussed above, US’284 also teaches modifications that can be made in the Fc domain including E233V, L234D, L235F, G236R, G237D, S239L, S267D, H268P, T299A, A327L, L328A, A330H, and E333I. As discussed above, US’371 teaches the mutation S298G in combination with T299A to increase FcγRIIa binding and the effector function of agonistic antibodies. These mutations, in the human IgG Fc domain of US’284, SEQ ID NO: 1 would result in a human IgG Fc domain that is identical to instant variant 2b18K of SEQ ID NO: 3.
While the prior art does not exemplify the Fc mutant, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to make a variant human IgG Fc domain in order to optimize binding of FcγR receptors using the modifications disclosed by US’284 and US’371 in the human IgG Fc domain disclosed by US’284. It would have been obvious to use the mutations disclosed by US’284 and US’371 as both references teach the substitutions as those that can be made in Fc regions of antibodies to enhance antibody function. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success. The conclusion of prima facie obviousness is further supported by KSR(E) obvious to try. See MPEP 2143. In this case, the combination of applied references teaches a finite number of substitutions that can be made in antibody Fc domains in order to improve functions. The art also provides experimental testing of the substitutions allowing for predictable modifications of the Fc domains. Therefore, one of ordinary skill in the art would have been able to pursue the known, potential solutions with a reasonable expectation of success.
Furthermore, it would have been obvious to an ordinarily skilled artisan to use the human IgG Fc domain and the substitutions disclosed in the prior art as a starting point for optimization that was routine in the art in order to achieve the desired Fc properties.
MPEP 2144.05 (II) A. states "’[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)” and "It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007)”.
In this case, the combination of applied references demonstrate that modification to Fc domains were routine in the art as were optimizing properties of the modified Fc domains using amino acid substitutions. Therefore, it would have been obvious to use the substitutions taught in the prior art as a starting point to determine the optimal Fc sequence for a given polypeptide application.
Regarding claims 21-24 and 53-55, the recited limitations are functional properties that are inherent to the amino acid sequence of the mutant Fc domain. As discussed above, the combination of US’284 and US’786 teach a parent domain and substitutions rendering instant SEQ ID NO: 3, or variant 2b18K, obvious. The functional properties recited in claims 21-24 are inherent to this amino acid sequence, as evidenced by the instant disclosure, Table 5 and [00222], and; therefore, would flow naturally from following the suggestions of the prior art. MPEP 2145 II. states “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” The MPEP section further states “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.”
Claims 10, 21, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0315284 A1 (Lazar, G.A., et al) 05 Nov 2015 as applied to claim 1 above, and in further view of US 2016/0376371 A1 (Ravetch, J., et al) 29 Dec 2016, US 2006/0275283 A1 (van Vlijmen, H., et al) 7 Dec 2006, and US 10,851,178 B2 (Bernett, M.J., et al) 1 Dec 2020.
US’284 teaches the polypeptide of claim 1 as discussed in detail above.
As discussed above, US’284 teaches the parent human IgG Fc domain SEQ ID NO: 1. US’284, SEQ ID NO: 1 has the following alignment with instant SEQ ID NO: 2.
PNG
media_image5.png
292
583
media_image5.png
Greyscale
As discussed above, US’284 teaches substitutions of E233V, L324P, L235T, S239L, S267D, H268H, T299A, A327L, L328A, and I332Q.
US’284, however, does not disclose the substitutions of K210E, S298G, or K334V.
The teachings of US’371 are as discussed above and, as discussed above, US’371 teaches the modification of S298G.
US’283 teaches the altering of effector functions mediated by an Fc-containing polypeptide by modifying one or more amino acid residues within the polypeptide. The polypeptides produced by the method are highly variable, and can include antibodies and fusion proteins that contain an Fc region or a biological portion thereof (abstract).
US’283 teaches a substitution at position 334, including K334V (page 3, [0065]; Page 5, [0151]). US’283 also provides data regarding the K334V mutation in a bridging assay with human FcγRIIb (CD32b) (page 5, [0151]; Fig. 4).
US’178 teaches engineered variants of constant regions and studied the impact of charge state on antibody pharmacokinetics in novel engineered variants in the constant regions to improve half life (col. 2, lines 26-30). US’178 teaches numerous IgG variants that comprise the K210E substitution. For instance, see SEQ ID NOs: 7, 11, 25-28, 35, 38, 41, 44, 47, 52-53, 57, and 68-70.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the human IgG Fc domain disclosed by US’284 to further comprise a mutation of S298G as disclosed by US’371, to further include a K334V mutation as disclosed by US’283 and a K210E substitution as disclosed by US’178. It would have been obvious to include these mutations as the prior art demonstrates that they were known substitutions that could be made in Fc regions in order to optimize effector function. An ordinarily skilled artisan would have had a reasonable expectation of success as all of US’284, US’371, US’283, and US’178 teach methods of modifying IgG Fc regions in order to optimize Fc effector functions. The conclusion of prima facie obviousness is further supported by KSR(E) obvious to try. See MPEP 2143. In this case, the combination of applied references teaches a finite number of substitutions that can be made in antibody Fc domains in order to improve functions. The art also provides experimental testing of the substitutions allowing for predictable modifications of the Fc domains. Therefore, one of ordinary skill in the art would have been able to pursue the known, potential solutions with a reasonable expectation of success.
Furthermore, it would have been obvious to an ordinarily skilled artisan to use the human IgG Fc domain and the substitutions disclosed in the prior art as a starting point for optimization that was routine in the art in order to achieve the desired Fc properties. See MPEP 2144.05 (II) A. In this case, the combination of applied references demonstrate that modification to Fc domains were routine in the art as were optimizing properties of the modified Fc domains using amino acid substitutions. Therefore, it would have been obvious to use the substitutions taught in the prior art as a starting point to determine the optimal Fc sequence for a given polypeptide application.
Regarding claims 21 and 23 the recited limitations are functional properties that are inherent to the amino acid sequence of the mutant Fc domain. As discussed above, the combination of US’284, US’371, US’283, and US’178 teach a parent domain and substitutions rendering instant SEQ ID NO: 2, or variant V8.2, obvious. The functional properties recited in claims 21 and 23 are inherent to this amino acid sequence, as evidenced by the instant disclosure, Table 5, and; therefore, would flow naturally from following the suggestions of the prior art. See MPEP 2145 II.
Claims 15 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0315284 A1 (Lazar, G.A., et al) 05 Nov 2015 as applied to claims 1 and 12-13 above, and in further view of US 2010/0184959 A1 (Guler-Gane G., et al) 22 Jul 2010.
US’284 teaches the polypeptide of claim 1 as discussed in detail above.
US’284, however, does not disclose that the Fc domain further comprises a substitution mutation of R292Q.
US’959 teaches methods for selecting, obtaining, or producing Fc variant polypeptides which show altered recognition for an Fc ligand, e.g., FcγR, CIq. Additionally, the Fc variant may have altered ADCC and/or CDC activity. US’959 further teaches methods and protocols for the application of the Fc variants, particularly for therapeutic purposes (abstract).
US’959 teaches methods in which a wild-type Fc polypeptide comprises one or more substitutions including 292Q, which is R292Q, and teaches this substitution in Fc polypeptides that are capable of binding to FcγRIIb (page 4, [0047]-[0049]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the polypeptide of US’284 to further include a R292Q substitution as disclosed by US’959. It would have been obvious to further include the R292Q mutation as US’959 teaches the substitution as an additional substitution that can be made in wild-type Fc polypeptides in order to alter effector activity by altering Fc ligand recognition for therapeutic purposes. An ordinarily skilled artisan would have had a reasonable expectation of success as both US’284 and US’959 both teach Fc modification as a means to optimize Fc containing therapeutics, demonstrating analogous art.
Claims 16, 18, 21-24 and 53-55 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0315284 A1 (Lazar, G.A., et al) 05 Nov 2015 in view of US 2010/0184959 A1 (Guler-Gane G., et al) 22 Jul 2010 as applied to claims 15 and 17 above, and in further view of US 2016/0376371 A1 (Ravetch, J., et al) 29 Dec 2016.
The combination of US’284 and US’959 teach the polypeptides of claims 15 and 17 as discussed in detail above.
As discussed above, US’284 teaches the parent human IgG Fc domain SEQ ID NO: 1. US’284, SEQ ID NO: 1 has the following alignment with instant SEQ ID NOs: 4 and 5, respectively:
PNG
media_image6.png
336
588
media_image6.png
Greyscale
PNG
media_image7.png
296
593
media_image7.png
Greyscale
As discussed above, US’284 also teaches modifications that can be made in the Fc domain including E233V, L234D, L235F, G236R, G237D, S239L, S267D, H268P, T299A, A327L, L328A, A330H, and E333I. As discussed above, US’959 teaches a substitution of R292Q.
The combination of US’284 and US’959, however, do not disclose the mutation of S298G, which is also present in the instant sequences.
The teachings of US’371 are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the polypeptide taught by the combination of US’284 and US’959 to further include a S298G mutation as taught by US’371. An ordinarily skilled artisan would have been motivated to further include the S298G mutation as US’371 teaches that such mutation, in combination with T299A, can restore effector function, increase signal strength, and the activation of cells. An ordinarily skilled artisan would have had a reasonable expectation of success as US’284 teaches the mutation T299A, which US’371 teaches in combination with the S298G mutation.
The conclusion of prima facie obviousness is further supported by KSR(E) obvious to try. See MPEP 2143. In this case, the combination of applied references teaches a finite number of substitutions that can be made in antibody Fc domains in order to improve functions. The art also provides experimental testing of the substitutions allowing for predictable modifications of the Fc domains. Therefore, one of ordinary skill in the art would have been able to pursue the known, potential solutions with a reasonable expectation of success.
Furthermore, it would have been obvious to an ordinarily skilled artisan to use the human IgG Fc domain and the substitutions disclosed in the prior art as a starting point for optimization that was routine in the art in order to achieve the desired Fc properties. See MPEP 2144.05 (II) A. In this case, the combination of applied references demonstrate that modification to Fc domains were routine in the art as were optimizing properties of the modified Fc domains using amino acid substitutions. Therefore, it would have been obvious to use the substitutions taught in the prior art as a starting point to determine the optimal Fc sequence for a given polypeptide application.
Regarding claims 21-24 and 53-55, the recited limitations are functional properties that are inherent to the amino acid sequence of the mutant Fc domain. As discussed above, the combination of US’284, US’959, and US’371 teach a parent domain and substitutions rendering instant SEQ ID NOs: 4 and 5, or variants 2b18KQ and 2b18KQS, obvious. The functional properties recited in claims 21-24 are inherent to these amino acid sequences, as evidenced by the instant disclosure, Table 5 and [00222], and; therefore, would flow naturally from following the suggestions of the prior art. See MPEP 2145 II.
Claims 32-44 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0315284 A1 (Lazar, G.A., et al) 05 Nov 2015 as applied to claim 1 above, and in further view of US 2004/0175786 A1 (Choi, I) 09 Sept 2004.
US’284 teaches the polypeptide of claim 1 as discussed in detail above.
As discussed above, US’284 teaches aglycosylated and glycosylated Fc domains, a T299A modification, and teaches that the Fc mutant human IgG Fc domains can be comprised in a multimeric oligomer. US’284 further demonstrates that position 309 in IgG1 Fc (SEQ ID NO: 1) is leucine (Leu, L), that position 298 is serine (ser, S), and that position 299 is threonine (Thr, T) (Fig. 3b-1 – 3b-2).7
US’284, however, does not disclose that the multimeric oligomer is a hexameric Fc fusion protein.
US’786 teaches the use of single chain antibodies in polymeric form, e.g., as a dimer, a tetramer, pentamer, hexamer, or a mixture thereof. These forms distinguish themselves over the monomeric ones by an increased avidity (page 2, [0011]). US’786 further teaches the incorporation of IgM tailpieces and the use of such tailpieces for polymerization of the antibody. It is demonstrated that the tailpiece influences polymerization pattern and antibody production while not substantially influencing binding specificity (page 1, [0005]).
Figure 2 of US’786 provides a schematic in which the tailpiece is shown as an addition to the end of the antibody Fc region (Fig. 2a) as well as tailpiece sequences that were tested (Fig. 2b) including IgA wt, three IgM variants, C575S, and VAEVD (page 3, [0023]-[0027]).
US’786, SEQ ID NO: 1, is the same as instant SEQ ID NO: 6, as shown in the ABSS alignment below:
PNG
media_image8.png
107
581
media_image8.png
Greyscale
US’786 further demonstrates the formation of hexamers using the sequence (Fig. 3).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the polypeptide of US’284 to comprise the mutant human IgG Fc domain in a multimeric oligomer, including a hexamer fusion protein using the tailpiece of US’786, SEQ ID NO: 1 as disclosed by US’786. An ordinarily skilled artisan would have been motivated to form a multimeric oligomer, such as a hexamer, in order to increase antibody avidity as disclosed by US’786. The modification is further motivated by US’284, which teaches that multimeric Fc polypeptides provide multiple binding sites for Fc receptors with a single protein molecule. An ordinarily skilled artisan would have had a reasonable expectation of success as US’284 teaches that the mutant human IgG Fc domains can be included in multimeric oligomers and US’786 teaches methods of making hexameric multimeric antibody oligomers, demonstrating analogous art.
Claims 45-46 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0315284 A1 (Lazar, G.A., et al) 05 Nov 2015 in view of US 2004/0175786 A1 (Choi, I) 09 Sept 2004 as applied to claim 37 above, and in further view of US 2010/0184959 A1 (Guler-Gane G., et al) 22 Jul 2010, US 2016/0376371 A1 (Ravetch, J., et al) 29 Dec 2016, and Rowley, T.F., et al (2018) Engineered hexavalent Fc proteins with enhanced Fc-gamma receptor avidity provide insights into immune complex interactions Communications Biology 1(146); 1-12.
The combination of US’284 and US’786 teach the polypeptide of claim 37 as discussed in detail above.
The combination of applied references, however, does not disclose that the hexameric Fc fusion protein comprises one of the recited SEQ ID NOs.
The teachings of US’959 and US’371 are as discussed above.
As discussed in detail above in the rejection of instant claim 18, the combination of US’284, US’959, and US’371 render obvious a polypeptide of instant SEQ ID NO: 5 and US’786 teaches the addition of a tailpiece of US’786, SEQ ID NO: 1 to the end of the Fc domain as a means to create a hexamer.
The combined teachings of US’284, US’786, US’959, and US’371 teach a sequence that is identical to instant SEQ ID NO: 7 with the exception of a single mutation in Kabat position 309 of L309C.
Rowley teaches the construction of Fc hexamers and, in Fig. 1, page 2, provides a schematic of the structure of Fc hexamers. Rowley teaches that Fc hexamers consist of the human IgG Fc hinge-CH2-CH3 domains fused to an IgM tailpiece domain, which provides stable hexamerization. In the schematic a L309C mutation is included which generates an additional cysteine bond. Rowley further teaches that the hexamers are generated by fusion of the human IgM tailpiece at the C terminal. Rowley teaches that the tailpiece has a sequence of PTLYNVSLVMSDTAGTCY (page 2, right column, paragraph 2), which is identical to the tailpiece taught by US’786.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the polypeptide disclosed by the combination of US’284 and US’786 to further include a R292Q substitution as disclosed by US’959, a S298G substitution as taught by US’371, and a L309C substitution as taught by Rowley. It would have been obvious to further include the R292Q mutation as US’959 teaches the substitution as an additional substitution that can be made in wild-type Fc polypeptides in order to alter effector activity by altering Fc ligand recognition for therapeutic purposes. An ordinarily skilled artisan would have had a reasonable expectation of success as both US’284 and US’959 both teach methods of optimizing Fc domains for therapeutic purposes. An ordinarily skilled artisan would have been motivated to further include the S298G mutation as US’371 teaches that such mutation, in combination with T299A, can restore effector function, increase signal strength, and the activation of cells. An ordinarily skilled artisan would have had a reasonable expectation of success as US’284 teaches the mutation T299A, which US’371 teaches in combination with the S298G mutation. It would have been obvious to introduce a L309C mutation as Rowley teaches this mutation in hexamers in addition to the IgM tailpiece as a means to form a disulfide bond. An ordinarily skilled artisan would have had a reasonable expectation of success as US’284 teaches that the mutant human IgG Fc domains can be included in multimeric oligomers and US’786 and Rowley teach methods of making hexameric multimeric antibody oligomers, demonstrating analogous art.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AUDREY L BUTTICE whose telephone number is (571)270-5049. The examiner can normally be reached M-Th 8:00-4:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached on 571-272-2911. 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.
/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693