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 .
DETAILED ACTION
Status of the Claims
1. Claims 1-59 are the original claims filed 11/21/2022. In the Preliminary Amendment of 6/16/2023, Claims 6, 8-9, 11, 13-14, 16-17, 19, 21-25, 27, 29-32, 34-36, 40, 42-45, 47-48, 54, and 56-58 are amended and claims 1-4, 46, and 49-52 are canceled. In the Response of 4/23/2026, Claims 5, 11, 17, 19, 21, 23, 24, 28-31 and 53 are amended, claims 6-10, 13-16, 20, 22, 25-27, 32-33 and 54-55 are cancelled, and new claims 60-62 are added.
Claims 5, 11-12, 17-19, 21, 23-24, 28-31, 34-45, 47-48, 53, and 56-62 are the claims.
Applicants’ amendment of the claims raises new grounds for objection and rejection. The Office Action is final.
Priority
2. USAN 17/999,477, filed 11/21/2022, is a National Stage entry of PCT/CA2021 /050691, International Filing Date: 05/20/2021, PCT/CA2021/050691 Claims Priority from Provisional Application 63/027,569, filed 05/20/2020, PCT/CA2021/050691 Claims Priority from Provisional Application 63/163,686, filed 03/19/2021.
Information Disclosure Statement
3. As of 5/12/2026, a total of five (5) IDS are filed: 11/21/2022; 7/11/2024; 7/26/2024; 9/5/2025; and 10/24/2025. The corresponding initialed and dated 1449 form is considered and of record.
Withdrawal of Objections
Specification
4. The objection to the disclosure because of informalities is withdrawn. Both clean and marked-up copies of the specification are filed.
a) The specification rectifies the improper use of the term Uniprot, Sepharose, Tween, Tris, BiaCore, GraphPad, MassHunter, Supelco, Chemstation, which is a trade name or a mark used in commerce.
b) The specification is amended in the figure legend to Figure 3 to include the sequence identifier for the peptides > 4 amino acids in length shown in the Figure.
c) The specification is amended in [00138] to include the sequence identifier for the peptides > 4 amino acids in length for 6xHis.
Claim Objections
5. The objection to Claims 5-45, 47-48 and 53-59 because of informalities is moot for the canceled claims and withdrawn for the pending claims.
a) Claims 5 and 53 are amended to recite "two or more stability-enhancing amino acid mutations" and to specify that the stability-enhancing amino acid mutations comprise "a mutation at position 287 which is a substitution with Phe, and one or more additional mutations selected from: a mutation at position 250 which is a substitution with Ala, Ile or Val, and a mutation at position 428 which is a substitution with Phe." Claim 5 is amended to recite "wherein the Fc variant has an increased CH2 domain melting temperature (Tm) as compared to the parental IgG Fc that does not include the two or more stability-enhancing amino acid mutations."
b) Claims 23-24 are amended to delete the use of symbols, e.g., 242C_336C and 287F/428F.
Withdrawal of Rejections
Claim Rejections - 35 USC § 112(b)
6. The rejection of Claims 5-45, 47-48 and 53-59 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is moot for the canceled claims and withdrawn for the pending claims.
a) Claims 5-45, 47-48 and 53-59 are amended to recite the variant Fc is based on a parental IgG Fc with a numbering of the amino acids according to the EU index.
Claim Rejections - 35 USC § 112(a)
Written Description
7. The rejection of Claims 32-33 and 54-55 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 is moot for the canceled claims.
Claim Rejections - 35 USC § 103
8. The rejection of Claim(s) 5-20, 23-45, 47-48 and 53-59 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lowman (WO 2006031370; 3/23/2006; IDS 11/21/2022) in view of Ruker (WO 2012032080; 3/15/2012 (IDS 11/21/2022), Hinton (US 8624007; 1/7/2014; IDS 11/21/2022), Liu (US 2014/0112926; IDS 11/21/2022) and Reyes (US 2012/0100140; 4/26/2012; IDS 11/21/2022) is moot for the canceled claims and withdrawn for the pending claims.
The amendment of the claims provides for an Fc variant based on an IgG Fc with improved CH2 domain thermostability comprising the mutations 287A in combination with 250A/I/V and/or 428F. The references alone and in combination do not teach the residue substitutions would increase CH2 domain thermostability in an IgG-based-Fc region.
New Grounds for Objection
Claim Objections
9. Claims 5, 11-12, 17-19, 21, 23-24, 28-31, 34-45, 47-48, 53, and 56-62 are objected to because of the following informalities:
a) Claims 5, 11-12, 17-19, 21, 23-24, 28-31, 34-45, 47-48, 53, and 56-62 are inconsistent for reciting “the parental IgG Fc”, “the Fc region” (Claims 30-31), “the parental Fc” (Claims 56-57), and “the parental Fc region” (claim 58).
b) Amend claim 5 to correct punctuation to recite “a mutation at position 287, which is a substitution with Phe.” Alternatively, amend claim 5 to replace “which” with “that.”
c) Amend claim 5 to delete duplicative subject matter that does not change the scope of the claim as follows: “wherein the Fc variant has an increased CH2 domain melting temperature (Tm) as compared to the parental IgG Fc
d) Amend claim 21 to correct punctuation to recite: “The Fc variant according to claim 5, wherein the two or more stability-enhancing mutations further comprise one or more mutations selected from:
a pair of mutations at position 242 and position 336, which are both substitutions with Cys;
a mutation at position 308, which is a substitution with Ile, and
a mutation at position 309, which is a substitution with Gln or Thr.
Alternatively, amend claim 21 to replace “which” with “that.”
e) Amend claims 40-41 to clarify whether an antigen-binding antibody fragment is a fragment of the same antibody in the corresponding claim.
f) Amend claim 53 to correct punctuation to recite: “a mutation at position 287, which is a substitution with Phe, and one or more additional mutations selected from: a mutation at position 250, which is a substitution with Ala, Ile or Val, and a mutation at position 428, which is a substitution with Phe, wherein the parental Fc is an IgG Fc, and wherein the numbering of amino acids is according to the EU index.”
Alternatively, amend claim 53 to replace “which” with “that.”
g) Amend claim 59 to recite “wherein the stability-enhancing amino acid mutations comprised by the Fc variant comprise 250V and 287F.” This comports with claims 23 and 24 that are each consistent with the other.
Appropriate correction is required.
New Grounds for Rejection
Claim Rejections - 35 USC § 112
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.
10. Claims 5, 11-12, 17-19, 21, 23-24, 28-31, 34-45, 47-48, and 60-62 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.
a) Claims 5, 11-12, 17-19, 21, 23-24, 28-31, 34-45, 47-48, and 60-62 are unclear and ambiguous for reciting “wherein the Fc variant is based on a parental IgG Fc that does not include the two or more stability-enhancing amino acid mutations” in claim 5. How the basis is determined and the structure of the basis for the Fc variant are not defined. Whereas with Claim 53 (not rejected), the Fc variant comprises the actual parental IgG Fc having mutations/substitutions introduced into the structure, per se. What forms the basis is indefinite.
See the specification that teaches a “basis” within the meaning of an Fc variant at
[0057] In certain embodiments, the Fc variant is based on an IgG, IgA, IgD, IgE or IgM Fc. In some embodiments, the Fc variant is based on a human IgG, IgA, IgD, IgE or IgM Fc. In some embodiments, the Fc variant is based on an IgG or IgA Fc. In some embodiments, the Fc variant is based on a human IgG or IgA Fc. In some embodiments, the Fc variant is based on an IgG Fc. In some embodiments, the Fc variant is based on a human IgG Fc.
[0058] In certain embodiments, the Fc variant is based on an IgG Fc, which may be an IgG1, IgG2, IgG3 or IgG4 Fc. In some embodiments, the Fc variant is based on a human IgG1, IgG2, IgG3 or IgG4 Fc. A sequence alignment of the human IgG1, IgG2, IgG3 and IgG4 CH2 and CH3 domains is provided in FIGS. 3A and 3B. In some embodiments, the Fc variant is based on an IgG1 Fc. In some embodiments, the Fc variant is based on a human IgG1 Fc.
Most notably, see the specification teaching that Fc variants of the invention are scaffolds based on an IgG1 Fc at
[0246] Variants and controls were prepared by site-directed mutagenesis and/or restriction/ligation using standard methods. The final DNA was sub-cloned into the vector pTT5 (see U.S. Pat. No. 9,353,382). All scaffolds used for preparation of the variants were based on an IgG1 Fc. The sequence of the IgG1 Fc region is provided in FIG. 1A. In certain clones, the C-terminal lysine residue was omitted from the Fc sequence.
“scaffold”: the specification teaching examples at
[0022] FIG. 2 shows the improvement in CH2 domain melting temperature (Tm) resulting from introducing exemplary stability-enhancing mutations into various Fc scaffolds (A) Scaffold 3 comprising asymmetrical mutations to promote heterodimeric Fc formation; (B) Scaffold 6 comprising N297A mutation, and (C) Scaffold 7 comprising S239D/I332E mutations. Scaffold 1 is a homodimeric IgG1 Fc.
The POSA cannot reasonably ascertain the full metes and bounds of the invention when the Fc variant could comprise any scaffold or any Fc region from any antibody isotype so long as it is “based” on a parental IgG Fc.
b) Claims 30 and 31 do not relate the additional mutations for improved function of the parental IgG Fc to the variant Fc of the invention. This rejection also ties into the rejection under section 10(a) herein above.
c) Claim 31 recites the limitation " the corresponding wild-type Fc". There is insufficient antecedent basis for this limitation in the claim. Claim 5 makes no reference to a wild-type Fc. Furthermore, claim 31 is unclear in how “the corresponding wild-type Fc” relates to “the parental IgG Fc” as both are recited in the claim.
d) Claims 60-62 are indefinite for failing to correlate the relationship of the additional mutations to the Fc variant decrease for aggregation under mildly acidic conditions.
Conclusion
11. No claims are allowed.
12. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu Julie can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LYNN A BRISTOL/Primary Examiner, Art Unit 1643
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