DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s amendment filed on June 4, 2026 is acknowledged.
Claims 1-43, 48, 49, and 51-57 have been canceled.
Claims 44-47 and 50 are pending and currently under consideration.
3. In view of applicant’s submission of a Terminal Disclaimer, the previous provisional nonstatutory double patenting rejection over claims in the copending USSN 18/427,146 has been withdrawn.
Note that USSN 18/427,146 is currently on appeal (Appeal 2026-001773).
4. 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.
5. 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.
6. Claims 44-46 and 50 are rejected under 35 U.S.C. 103 as being unpatentable Leger (WO 2018/073185, reference on IDS) in view of Adam (US 2006/0067930, reference on IDS) for the reasons of record.
The previous Office Action states:
“Leger et al. teach a canine IgG Fc domain comprising amino acid substitutions (e.g. see Abstract and page 8). Leger et al. teach the amino acid sequences of the wild type canine IgB, IgD, and IgA (e.g. see Figure 8). Leger et al. teach a canine IgG Fc domain having increased binding affinity to canine FcRn compared to the parent canine IgG without amino acid substitution (e.g. see page 7). Leger et al. identified N434 as one of the seven residues belonging to the binding interface of the native canine Fc/FcRn complex (e.g. see Figure 8 and its legend in page 33). N434 is conserved between all canine IgG and human IgG.
Leger et al. teach that human Fc variants comprising M252Y/S254T/T256E (the YTE mutant) and H433K/N434F/Y436H were known in the art to improve IgG1-huamn FcRn complex stability (e.g. see page 3). Leger et al. teach full length antibody (e.g. in page 12) which would be understood as encompassing six CDRs.
Leger et al. teach examples of a canine IgG B Fc variant having the YTE (adopted from human YTE) substitutions in the Fc region and show that the Fc variant displayed increase binding to FcRn at pH6.0 as compared to the parent Fc (e.g. see page 4 and Examples in pages 33-49).
Leger et al. teach examples of a canine IgG B Fc variant consists of N114A substitution (corresponding to N434A in EU numbering) in Example 2 in page 37 and shows that this Fc variant binds canine FcRn better than wild type IgG (e.g. see page 38). Ledger et al. teach that the antibody variant can be purified with sodium citrate buffer and neutralized suing Tris buffer and dialyzed into PBS, a well-known pharmaceutically acceptable excipient (e.g. see lines 15-25 in pages 18, 31, and 35).
The reference teachings differ from the instant invention by not describing His at position 434 of the canine IgG Fc region.
Adam et al. teach an antibody comprising a human IgG Fc wherein the amino acid residue N434 is substituted with amino acid residue Trp (W), Tyr (Y), or His (H), wherein the Fc region has higher affinity than native unmutated IgG Fc sequence at pH6.0 (e.g. see claim 72 and FIGs. 8 and 13). Adam et al. further teach that the Fc can be from dog (e.g. see [0138]). Adam further teaches that the antibody can be formulated into a pharmaceutical composition comprising a pharmaceutically acceptable excipient (e.g. see [0053]).
It would thus be obvious to one of ordinary skill in the art at the time the invention was filed to produce a canine IgG B antibody Fc variant by performing amino acid substitution in position 434 to replace the naturally occurring amino acid residue asparagine (N, conserved in human and canine) with histidine for increased binding to FcRn. An ordinary skill in the art would have been motivated to do so, and have a reasonable expectation of success, since Adam et al. and Leger et al. both teach Fc variant comprising amino acid substitution in position N434 in human IgG1 Fc region could enhance the Fc’s affinity to FcRn and Adam teaches human IgG Fc consisting of N434H substitution result in an Fc variant with enhanced affinity to FcRn. Such canine antibody Fc variant would be expected to have the benefit of prolonged serum half life.
Given that Leger teaches that canine IgG B YTE mutant was shown to have the same effect of enhanced binding to FcRn as what was shown in human IgG1 Fc variant comprising YTE mutant, and since Leger teaches that N434 is conserved in canine IgG B (as the human IgG1 Fc region), an ordinary skill in the art would have been motivated to mutate amino acid residues in position N434 with amino acid residues H in the canine anti- Ig B antibody Fc region following well-established point mutation methods as shown in Adam and Leger, with a reasonable expectation of success to produce an canine IgB Fc variant comprising/consisting of amino acid substitution N434H.
Such canine Ig B antibody Fc variant would be expected to inherently/intrinsically exhibit the function of binds to a canine FcRn at higher level at an acidic pH than at a neutral pH and suitable for veterinary use”
Applicant’s arguments in conjunction with the Brondyk declaration under 37 CFR 1.132 have been fully considered but have not been found persuasive.
Applicant asserts that the inventor surprising discovered that a canine IgG Fc region N434H has increased binding affinity to canine FcRn compared to wild-type Fc region at pH5.5 as shown in Table 12 in the specification as-filed.
The Brondyk declaration asserts that 142 canine IgG Fc region variants were tested and only 6 variants including N434H led to increased binding affinity as set forth in Example 2 of the specification as-filed. Thus, applicant asserts it is unpredictable and a person of skill in the art would not have been motivated to mutate amino acid residue at position N434 in canine Fc and there is no reasonable expectation of success to produce a canine Fc variant comprising amino acid substitution in N434. The Brondyk declaration further asserts that known mutations that increase affinity in human Fc do not result in higher affinity for canine IgG Fc in positions such as T250Q in positions that are conserved between human and canine Fc including positions 250, 311, 380, and 434 as disclosed in Tables 4 and 6-11 in the instant specification as-filed.
Furthermore, the Brondyk declaration states Leger does not teach N434H mutation in human or canine but only teaches N434A alone or in combination with other substitutions in the Fc region and does not teach off-rate or Kd value of N434A substitution. Ledge teaches when N434A was combined with other mutations, it lowers the binding compared to wild type Fc. Leger would motivate a skill in the art to produce YTE mutant but not N434 mutation in canine. Adams teaches N434A substitution in human that leads to a larger increase in binding affinity in human IgG Fc than canine IgG Fc region.
Brondyk declaration asserts that the instant application disclosed substitutions in N434 in the Fc region of canine IgG and teach N434Y, N434W, N434R, N434H but not N434A or N434S exhibits higher affinity to canine FcRn in Table 11 and 12 in the specification as-filed.
Brondyk declaration states that the teachings of Leger and Adams would lead to the understanding that there is unpredictability in applying the results from the human IgG Fc study to canine IgG Fc region and same substitution can alter the binding to different degrees or even to in a different direction.
Moreover, applicant argues that evidence supporting unpredictability is also show in Table copied below:
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400
668
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Applicant argues that conservative substitution does not support predictability because Zalevsky and Chamberlain both teaches that M428L and N434S in human IgG1 or IgG2 lead to 11-fold or 14-fold improvement in FcRn affinity while Nakao teaches that the same mutations in canine only yield 2-fold improvement in canine FcRn binding. Applicant further listed other mutations to support unpredictability. Applicant asserts that Leger teaches against cross-species extrapolation in pages 3-4.
Applicant asserts that it was unexpected that among the six substitutions made in position 434, only N434Y, N434W, N434R, N434H exhibits increased binding to FcRn but not N434A and N434S.
As such, applicant asserts that the rejection should be withdrawn.
This is not found persuasive for following reasons:
Contrary to applicant and the Brondyk declaration’s arguments that there is no motivation and expectation of success based on the teachings of the prior art, note that it is not required that the prior art specifically teaches and produces N434H substitution in canine IgG Fc region in order to provide motivation and expectation of success to one of ordinary skill in the art. All that is required is a reasonable expectation of success, not absolute predictability of success. See In re O’Farrell, 853 F.2d 894,903 (Fed. Cir. 1988).
Here, Leger teach that major improvements in the IgG1-human FcRn complex stability occur in substituting residues located in a band across the Fc-FcRn interface including finite number of residues M252, S254, T256, H433, N434, and Y436 (e.g. see lines 7-9 in page 3). Leger teaches working example of N434A substitution in the Fc region of canine IgG (corresponding N114A substitution, also referred to as NA mutant) that shows increased binding to FcRn than unmutated canine Fc (e.g. see Example 2).
While canine and human IgG Fc regions are different, Leger specifically teaches comparing the amino acid sequences of the canine IgG Fc to that of a human IgG Fc and identify the conserved sequences between the two species (e.g. see lines 23-32 in page 48 and Figure 8) and generated molecular modeling of the complex of canine Fc/FcRn based on crystal structure of YTE human Fc variant in complex with human FcRn and human serum albumin (e.g. see Example 4 in page 47).
It is noted that in considering the disclosure of a reference, it is proper to take into account not only specific teaching of the reference but also the inferences which one skilled in the art would be reasonably be expected to draw therefrom In re Preda, 401 F.2d 825, 159 USPQ 342, 344 (CCPA 1968). See MPEP 2144.01.
Here, it is known that the human IgG Fc sequences can be used to provide a road map for canine Fc variant. For example, Leger discloses sequence alignments of canine IgG and human IgG Fc and boxed mutually identical sequences including N434 which is conserved in human IgG Fc and canine IgG Fc, and also highlighted the residues belonging to the binding interface of Fc/FcRn (e.g. see page 33 and Figure 8).
While one of skill in the art would recognize there are major sequence difference in other regions between human and canine Fc, the conserved residues in position N434 between the two species and the N434A substitutions in both human and canine Fc regions enhanced binding affinity to human and canine FcRn, respectively, would motivate one of skill in the art to follow well-documented methods of making amino acid substitutions in position N434 in the canine Fc region and perform routine experiments to select the canine Fc variants with enhanced binding to canine FcRn.
Given that Adam et al. and Leger et al. both teach Fc variant comprising amino acid substitution in position N434 in human IgG1 Fc region could enhance the Fc’s affinity to FcRn and Adam et al. teach human IgG Fc consisting of N434H or N434W or N434Y result in an Fc variant with enhanced affinity to FcRn, an ordinary skill in the art would have been motivated to mutate N434H in the Fc region of a canine antibody and would be expected to have the benefit of binds to a canine FcRn at higher level at pH5.5 than at pH7.4.
Further, in contrast to applicant and the Brondyk declaration’s assertion of unexpected results because some substitutions in N434, e.g. N434S, does not show enhanced FcRn binding, note that applicant’s own work support the results disclosed by Adam et al. that teaches N434H or N434W or N434Y in human Fc region enhanced FcRn binding.
"There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art." Motorola, Inc. v. Interdiqital Tech. Corp., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Given that Leger et al. follow the observation of human IgG1 by producing YTE mutant in canine IgG B and observed the same effect of enhanced binding to FcRn as what was shown in human IgG1 Fc variant comprising YTE mutant, and since Leger et al. expressly teach that N434 is conserved in canine IgG B (as the human IgG1 Fc region), an ordinary skill in the art would have been motivated to mutate amino acid residues in position N434 with amino acid residues H in a polypeptide comprising a canine IgG Fc region following well-established point mutation methods as shown in Adam et al. and Leger et al., with a reasonable expectation of success to produce an canine IgB Fc variant comprising/consisting of amino acid substitution N434H.
As such, applicant’s arguments have not been found persuasive.
7. Claim 47 is rejected under 35 U.S.C. 103 as being unpatentable over Leger (WO 2018/073185) in view of Adam (US 2006/0067930) as applied to claims 44 and 45 above, and further in view of Li (WO 2018/156180, reference on IDS) for the reasons of record.
Applicant’s arguments and the Examiner’s rebuttal regarding the teachings of Leger and Adam are essentially the same as shown above.
Applicant further argues that Li teaches canine anti-IL-31 antibody but does not teach mutations N434H in the Fc region. Thus, applicant argues that the rejection should be withdrawn.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Here, as stated previously, given that Leger teaches that canine IgG B YTE mutant was shown to have the same effect of enhanced binding to FcRn as what was shown in human IgG1 Fc variant comprising YTE mutant, and since Leger teaches that N434 is conserved in canine IgG B (as the human IgG1 Fc region), an ordinary skill in the art would have been motivated to mutate amino acid residues in position N434 with amino acid residues H in the known canine anti-IL-31 Ig B antibody Fc region taught by Li following well-established point mutation methods as shown in Adam and Leger, with a reasonable expectation of success to produce an canine IgB Fc variant comprising/consisting of amino acid substitution N434H.
8. No claim is allowed.
9. THIS ACTION IS MADE FINAL. 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.
10. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHUN DAHLE whose telephone number is (571)272-8142. The examiner can normally be reached Mon-Fri 6:30am-4:00pm.
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, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHUN W DAHLE/Primary Examiner, Art Unit 1641
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