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 .
Status of the Claims
1. Claims 1-15 are the original claims filed 11/18/2022. In the Preliminary Amendment of 5/15/2023, claims 3-7, 9, and 14 are amended. In the Response of 1/20/2026, claims 1, 3-5, and 10-13 are amended, claims 2 and 14 are cancelled, and claims 16-18 are added.
Claims 1, 3-13, and 15-18 are all the claims.
The amendment of the abstract and claims raises new grounds for objection and rejection. The Office Action is final.
Priority
2. USAN 17/926,283, filed 11/18/2022, is a National Stage entry of PCT/NL2021/ 050322, International Filing Date: 05/20/2021, claims foreign priority to EP 20175903.2, filed 05/21/2020.
Information Disclosure Statement
3. As of 3/18/2026, a total of two (2) IDS are filed: 11/18/2022; and 12/8/2023. The corresponding initialed and dated 1449 form is considered and of record.
Withdrawal of Objections
Specification
4. The objection to the abstract of the disclosure is withdrawn. The abstract is amended to describe the improvement made by the invention.
5. The objection to the disclosure because of informalities is withdrawn.
a) The amended specification rectifies the improper use of the term, i.e., ATCC, Octet, DART, LABCHIP, Perkin Elmer, Protein Express, TSKgel, Agilent, Chemidoc, which is a trade name or a mark used in commerce.
b) The specification is amended to correct the misspelling for LABCHIP.
c) The specification is amended to delete the embedded hyperlink and/or other form of browser-executable code. See p. 25, line 5.
Claim Objections
6. The objection to Claims 1-15 because of informalities is moot for the canceled claims and withdrawn for the pending claims.
a) Claims 1-15 are amended to replace the term “variant” with “substitution.”
b) Claims 1-15 are amended to recite “at position K360, S364, and/or K409.”
d) Claim 1 is amended to recite “further comprises
e) Claim 3 is amended to correlate “a human IgG1, an IgG2, an IgG3 or an IgG4 CH3-region” to the first polypeptide and second polypeptide of claim 1.
Withdrawal of Rejections
Claim Rejections - 35 USC § 112(b)
7. The rejection of Claims 4-5 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
a) Claim 4 is amended to recite the broad recitation “human immunoglobulin Fc region”, and to delete the phrase “an IgG1, an IgG2, an IgG3, or an IgG4 Fc region”, which is the narrower statement of the range/limitation.
b) Claim 5(c) is amended to recite “one or more antibody light chains”, and to delete the phrase “the antibody light chain is a common antibody light chain”, which is the narrower statement of the range/limitation.
Claim Rejections - 35 USC § 112(d)
8. The rejection of Claims 2 and 14 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form is moot for the canceled claims.
Claim Rejections - 35 USC § 102
9. The rejection of Claim(s) 1, 3-13 and 15 under 35 U.S.C. 102(a)(1) as being anticipated by de Nardis et al (J Biol Chem. 2017 Sep 1;292(35):14706-14717. Epub 2017 Jun 27; IDS 12/8/2023) is withdrawn. Claims 1 and 10 are amended to incorporate the subject matter, inter alia, of canceled claims 2 and 14.
Objections Maintained
Claim Objections
10. The objection to Claims
a) AS regards Claims IgG1, applicants allege the CH3 sequence alignments from Fig. 33d EP3489262A1 show “high level of conservation between IgG isoforms.”
Response to Arguments
At least for residue R409 of human IgG4, the IgG4 isotype is dispositive to the allegation that the CH3 sequence corresponding to isotype IgG1, IgG2, IgG3 and IgG4 are highly conserved.
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b) AS regards claims 9 and 15, Applicants allege the phrase “that allow expression” is clear to the POSA.
Response to Arguments
Amend Claim 9 to replace the phrase “that allow expression” with the positive phrase “that induce expression.” See [0188] in the specification.
c) As regards Claim 4, Applicants allege the amendments to the claim overcome the objection (without explanation).
Response to Arguments
Claims 4 and new dependent claims 16-17 are indefinite for the phrase “the first and the second human IgG CH3-containing polypeptides comprise a human immunoglobulin Fc region.” That a CH3 domain is inherent to an Fc region suggests that the 1st and 2nd polypeptides each contain 2 CH3 domains, one of which is substituted while the other is not. Clarification is requested.
The objections are maintained.
Rejections Maintained
Claim Rejections - 35 USC § 103
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.
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.
11. The rejection of Claim(s)
a) Applicants allege the technical effect of the additional substitutions according to the present invention is an improved efficiency of heterodimer interaction, when compared to the efficiency of only the DEKK substitutions containing heterodimer (Page 9, line 3-7 of the PCT specification). Another technical effect is that the additional substitutions result in a lower efficiency of homodimer formation and more halfbody production than homodimer formation compared to the DEKK heterodimer (Page 9, lines 13-16 of the PCT specification). See Example 3, and tables 12-14 of the current application.
Response to Arguments
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).
It is maintained that the combination of references motivates and reasonably enables the success in achieving the claimed CH3-CH3 interface substituted heterodimers. The claims are not examined in light of only de Nardis that teaches a DEKK heterodimer and at least an S364 substitution.
Examples under the decision of KSR, 550 U.S. at 418, 82 USPQ2d at 1396 to support a conclusion of obviousness include
“Obvious to try” – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success.
Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention- the teaching of de Nardis and De Kruif to generate stable heterodimers from a limited number of CH3-CH3 interface residues and substitutions thereof that are overlapping is provided in each of the references:
De Kruif:
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de Nardis:
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b) Applicants allege that based on the teaching of interface residues within the CH3 regions, or the teaching of promising substitute candidate residues in De Kruif, a skilled person would not be motivated to introduce further substitutions at positions S364 or K409 or K360 in a heterodimeric protein with DEKK substitutions, let alone use the specific substitutions as recited in the claims. Neither of the cited prior art provides any pointers to the specific substitutions namely S364, K409 and/or K360 as claimed to further improve the efficiency of heterodimer formation and reduce the stability of homodimer formation of a DEKK containing heterodimer.
Response to Arguments
De Kruif specifically teaches at (103) the same DEKK motif for CH3-CH3 substituted heterodimers as does de Nardis:
Yet another preferred embodiment provides a heterodimeric antibody comprising two CH3 domains, wherein one of said two CH3 domains comprises the amino acid substitutions L351D and L368E and wherein the other of said two CH3 domains comprises the amino acid substitutions T366K and L351K. These amino acid substitutions are preferred means for preferential pairing of said two CH3 domains, as explained before. The amino acid substitutions L351D and L368E in one of said two CH3 domains and the amino acid substitutions T366K and L351K in the other of said two CH3 domains are together dubbed the ‘DEKK combination of mutations’, ‘DEKK variant’, ‘DEKK pair’, ‘DEKK engineered CH3 domains’, ‘DEKK’ or alternative names referring to DEKK are used. The CH3 domain that carries the amino acid substitutions L351D and L368E is also dubbed ‘the DE-side’ and the CH3 domain that carries the amino acid substitutions T366K and L351K is also dubbed ‘the KK-side’.
De Kruif does not teach away from combining residue substitutions for S364, K360 or K409, but instead motivates for the addition of the DEKK residues that are art-known for facilitating heterodimer formation.
De Kruif teaches and motivates by example for improved heterodimeric pairing by additional CH3 residue substitutions at (81) and (83) using conventional methods to engineer substitutions and test for improved heterodimer pairing.
De Kruif teaches and motivates by example for improved stability at (104-107) using conventional methods to engineer substitutions and test for improved heterodimer pairing.
c) Applicants allege a skilled person, based on the combined teachings of de Nardis and de Kruif, will have no reasonable expectation of success that adding further substitutions to a heterodimeric protein with DEKK substitutions would lead to the technical effects as presented in the current invention.
Response to Arguments
The cited references do not teach or suggest that further investigation is ill-advised, dangerous, or illogical, and that serves as evidence of "teaching away”. The prior art does teach away from the claimed invention, suggest a substitution that would destroy an advantageous property, or imply that further research is unlikely to succeed. MPEP § 2143.01 states that a prima facie case of obviousness is not established if the proposed modification renders the prior art inoperable, changes its principle of operation, or if the prior art "criticizes, discredits, or otherwise discourages" the solution claimed. "Obvious to Try" Limitations: While KSR allows an "obvious to try" rationale, it is limited to scenarios with a "finite number of identified, predictable solutions" and a "reasonable expectation of success." If the prior art discourages further testing, this expectation of success is absent. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375 (Fed. Cir. 2019).
The rejection is maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
12. The rejection of amended Claims 1, 3-13, and 15-18 on the ground of nonstatutory double patenting as being unpatentable over claims 1-40 of U.S. Patent No. 9248182 is moot for the canceled claims and maintained further in view of de Nardis et al (J Biol Chem. 2017 Sep 1;292(35):14706-14717. Epub 2017 Jun 27; IDS 12/8/2023) in view of De Kruif et al., (US 9248182; issued 2016-02-02) or (US 9758805; issued 2017-09-12) or (US 10329596; issued 2019-06-25) or (US 10337045; issued 2019-07-02).
The legal framework that governs arguing a nonstatutory double patenting rejection on the merits is set forth in Graham v. John Deere Co. of Kansas City. 383 US 1 (1966). See the grounds for rejection for obviousness set forth above under section 11. The additional substitutions to CH3-CH3 interface to improve heterodimerism, stability and purity are within the ordinary skill of the artisan and based on the limited variant residues and the range of substitutions taught in the combined references.
13. The rejection of amended Claims 1, 3-13, and 15-18 on the ground of nonstatutory double patenting as being unpatentable over claims 1-43 of U.S. Patent No. 9758805 is moot for the canceled claims and maintained further in view of de Nardis et al (J Biol Chem. 2017 Sep 1;292(35):14706-14717. Epub 2017 Jun 27; IDS 12/8/2023) in view of De Kruif et al., (US 9248182; issued 2016-02-02) or (US 9758805; issued 2017-09-12) or (US 10329596; issued 2019-06-25) or (US 10337045; issued 2019-07-02).
The legal framework that governs arguing a nonstatutory double patenting rejection on the merits is set forth in Graham v. John Deere Co. of Kansas City. 383 US 1 (1966). See the grounds for rejection for obviousness set forth above under section 11. The additional substitutions to CH3-CH3 interface to improve heterodimerism, stability and purity are within the ordinary skill of the artisan and based on the limited variant residues and the range of substitutions taught in the combined references.
14. The rejection of amended Claims 1, 3-13, and 15-18 on the ground of nonstatutory double patenting as being unpatentable over claims 1-34 of U.S. Patent No. 10329596 is moot for the canceled claims and maintained further in view of de Nardis et al (J Biol Chem. 2017 Sep 1;292(35):14706-14717. Epub 2017 Jun 27; IDS 12/8/2023) in view of De Kruif et al., (US 9248182; issued 2016-02-02) or (US 9758805; issued 2017-09-12) or (US 10329596; issued 2019-06-25) or (US 10337045; issued 2019-07-02).
The legal framework that governs arguing a nonstatutory double patenting rejection on the merits is set forth in Graham v. John Deere Co. of Kansas City. 383 US 1 (1966). See the grounds for rejection for obviousness set forth above under section 11. The additional substitutions to CH3-CH3 interface to improve heterodimerism, stability and purity are within the ordinary skill of the artisan and based on the limited variant residues and the range of substitutions taught in the combined references.
15. The rejection of amended Claims 1, 3-13, and 15-18 on the ground of nonstatutory double patenting as being unpatentable over claims 1-56 of U.S. Patent No. 10337045 is moot for the canceled claims and maintained further in view of de Nardis et al (J Biol Chem. 2017 Sep 1;292(35):14706-14717. Epub 2017 Jun 27; IDS 12/8/2023) in view of De Kruif et al., (US 9248182; issued 2016-02-02) or (US 9758805; issued 2017-09-12) or (US 10329596; issued 2019-06-25) or (US 10337045; issued 2019-07-02).
The legal framework that governs arguing a nonstatutory double patenting rejection on the merits is set forth in Graham v. John Deere Co. of Kansas City. 383 US 1 (1966). See the grounds for rejection for obviousness set forth above under section 11. The additional substitutions to CH3-CH3 interface to improve heterodimerism, stability and purity are within the ordinary skill of the artisan and based on the limited variant residues and the range of substitutions taught in the combined references.
16. The rejection of amended Claims 1, 3-13, and 15-18 on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 11926859 is moot for the canceled claims and maintained further in view of de Nardis et al (J Biol Chem. 2017 Sep 1;292(35):14706-14717. Epub 2017 Jun 27; IDS 12/8/2023) in view of De Kruif et al., (US 9248182; issued 2016-02-02) or (US 9758805; issued 2017-09-12) or (US 10329596; issued 2019-06-25) or (US 10337045; issued 2019-07-02).
The legal framework that governs arguing a nonstatutory double patenting rejection on the merits is set forth in Graham v. John Deere Co. of Kansas City. 383 US 1 (1966). See the grounds for rejection for obviousness set forth above under section 11. The additional substitutions to CH3-CH3 interface to improve heterodimerism, stability and purity are within the ordinary skill of the artisan and based on the limited variant residues and the range of substitutions taught in the combined references.
17. The rejection of amended Claims 1, 3-13, and 15-18 on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 12123043 is moot for the canceled claims and maintained further in view of de Nardis et al (J Biol Chem. 2017 Sep 1;292(35):14706-14717. Epub 2017 Jun 27; IDS 12/8/2023) in view of De Kruif et al., (US 9248182; issued 2016-02-02) or (US 9758805; issued 2017-09-12) or (US 10329596; issued 2019-06-25) or (US 10337045; issued 2019-07-02).
The legal framework that governs arguing a nonstatutory double patenting rejection on the merits is set forth in Graham v. John Deere Co. of Kansas City. 383 US 1 (1966). See the grounds for rejection for obviousness set forth above under section 11. The additional substitutions to CH3-CH3 interface to improve heterodimerism, stability and purity are within the ordinary skill of the artisan and based on the limited variant residues and the range of substitutions taught in the combined references.
New Grounds for Objection
Specification
18. The abstract of the disclosure is objected to because it contains legal language, i.e., “said.”
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Objections
19. Claims 9-13 and 15 are objected to because of the following informalities:
a) Claims 9-13 and 15 are inconsistent in their expression for the phrase “comprising _” (Claims 9, 12-13 and 15) versus “the method comprising _” (Clams 10-11). Amendment of the claims to recite “the method comprising _” is preferred.
b) Claims 9-12 and 15 are inconsistent with claim 13 (not herein objected to) for failing to recite an active method step that reflects determining the outcome in the preamble of the corresponding claim. Whereas Claim 13 recites in step “(b) subjecting the heterodimeric protein to ion exchange chromatography” in order to increase the purity of a heterodimeric protein, none of claims 9-12 recite an active step.
c) Amend claims 13 to replace “a)-c)” with “i)-iii).’
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.
20. Claims 4 and 16-17 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.
Claim 4 (and dependent claims 16-17) is indefinite for the phrase “the first and the second human IgG CH3-containing polypeptides comprise a human immunoglobulin Fc region.” That a CH3 domain is inherent to an Fc region suggests that the 1st and 2nd polypeptides each contain 2 CH3 domains, one of which is substituted while the other is not. Clarification is requested.
Conclusion
21. No claims are allowed.
22. 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.
23. 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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LYNN ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643