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
Continued Examination Under 37 CFR 1.114
1. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/22/2026 has been entered.
Status of the Claims
2. Claims 1-25 are the original claims filed 9/30/2022. In the Preliminary Amendment of 1/12/2023, claims 3-20, 22 and 24 are amended and claim 25 is canceled. In the Response of 2/9/2026, Claims 1, 7, 9-17 and 19 are amended and Claims 2 and 8 are canceled. In the Response of 7/22/2026, claims 1, 3, 6 and 23 are amended and claim 5 is canceled.
Claims 1, 3-4, 6-7 and 9-24 are all the claims.
The Office Action contains new grounds for rejection.
Priority
3. USAN 17/937,440, filed 09/30/2022, and having 1 RCE-type filing therein, is a Continuation of PCT/EP2021/058439, filed 03/31/2021, claims foreign priority to EP 20167624.4, filed 04/01/2020.
Information Disclosure Statement
4. As of 8/30/2026, a total of three (3) IDS are filed: 1/23/2023; 6/6/2025; and 7/22/2026. The corresponding initialed and dated 1449 form is considered and of record.
Withdrawal of Objections
Claim Objections
5. The objection to Claim 23 because of informalities is withdrawn.
a) Claim 23 is amended to replace “suitable” language with “is expressed”.
Withdrawal of Rejections
Claim Rejections - 35 USC § 112(b)
6. The rejection of Claims 1, 3-7 and 9-24 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is moot for canceled claim 5 and withdrawn for the pending claims.
Claims 1, 3-7 and 9-24 are amended to clarify the amino acid sequence EPKSC (SEQ ID NO: 6) is the C-terminal end of the unmodified cross-fab fragment of the CH1 domain (element (c) of claim 1).
7. The rejection of Claim 5 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 claim.
Withdrawal of Rejections
Claim Rejections - 35 USC § 103
8. The rejection of Claims 1, 5-7 and 9-24 under 35 U.S.C. 103 as being obvious over Amann et al (US 10526413; filed 11/14/2019; issued 1/7/2020) is moot for canceled claim 5 and withdrawn for the pending claims. Applicants allege Amann does not disclose “any of EPKSCG, EPKSCDK, or EPKSCDKTHL. As such, Amann does not teach or suggest all limitations of the amended claims.”
Rejections Maintained
Double Patenting
9. The rejection of Claims 1-12 and 16-24 on the ground of nonstatutory double patenting as being unpatentable over claims 10-14 of U.S. Patent No. 11780919 withdrawn.
10. The provisional rejection of Claims 1-24 on the ground of nonstatutory double patenting as being unpatentable over claims 13-23 of copending Application No. 18/457,729 (reference application US 20240117049) is withdrawn.
New Grounds for Rejection
Claim Rejections - 35 USC § 112
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.
Written Description
11. Claims 1, 3-4, 6-7 and 9-24 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.
Claims 1, 3-4, 6-7 and 9-24 are drawn to a bispecific construct comprising two Fabs (a) and (b) of Claim 1 that bind a 1st antigen with each Fab fused to the N’ of a Fc domain, a third Fab (c) of claim 1 comprising a cross-fab fragment as between the CH and CL regions where the wild type C’ of the CH1 ends with EPKSC and a modified C’ of the CH1 ends with EPKSCG, EPKSCDK, or EPKSCDKTHL where the property conferred by the universal C-terminal- modified cross-fab CH1 is reduced or no reactivity towards pre- existing anti-drug antibodies compared to the wild-type control.
Summary of species disclosed in the specification
The POSA is required to visualize the universe of generic bispecific antibodies that are defined by a de minimus structural feature, a namely, the C-most terminal end of a generic CH1 domain, that meets the functional requirement of the “wherein” clause for claim 1. The interpretation encompasses a genus of bispecific antibody constructs beyond those taught in the specification. A description adequate to satisfy 35 U.S.C. § 112(a) must clearly allow persons of ordinary skill in the art to recognize that the inventor invented what is claimed (Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc) (citation omitted, alteration in original). The purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent’s specification” (In re Katz Interactive Call Processing Patent Litig. 639 F.3d 1303, 1319 (Fed. Cir 2011).
Are the disclosed species representative of the claimed genus?
The specification teaches C-terminal extension variants for the bispecific constructs of the invention to evaluate reactivity toward preexisting anti-drug antibodies. The specification does not support a universal CH1 terminating with just any instant claimed extension of the wildtype sequence EPKSC having reduced or eliminated reactivity towards ADA. Most notably, the extent of C-terminal extension of the CH1 domain is performed on two prototypes: (MOXR0916) x FAP (1G1a) and GITR x FAP (4B9).
[0446] To evaluate the C-terminal extension variants of antigen binding molecules OX40 (49B4) x FAP (1G1a) (3+1), the same panel of human individual serum samples was tested (FIG. 18A) and its individual background signal substracted (FIG. 18C). The individual background signal was measured by performing the assay without the drug molecule (FIG. 18B).
(MOXR0916) x FAP (1G1a) prototype:
[0447] An extension of the C-terminus by naturally occurring aspartate at this position of the upper hinge region was generated in the molecule OX40 (MOXR0916) x FAP (1G1a) (3+1) (P1AF4845) (FIG. 19B). This modification resulted in a reduction of preexisting IgG reactivity compared to the molecule P1AE8786 with a free C-terminus (FIG. 19A). To eliminate the preexisting IgG reactivity completely, a variant with a C-terminal serine was generated. This serine is not naturally located at this position of the upper hinge region. The extension of the C-terminus by a serine of molecule P1AF4851 led to a complete elimination of the preexisting IgG reactivity, as shown in FIG. 19C.
[0448] FIGS. 20A to 20C show a respective molecule set in 2+1 format, and confirm the previous results that a C-terminal extension of an aspartate (Molecule OX40 (MOXR0916) x FAP (1G1a) (2+1) with EPKSCD (SEQ ID NO: 3) terminus, P1AF4852, FIG. 20B) reduces, while a C-terminal serine (molecule OX40 (MOXR0916) x FAP (1G1a) (2+1) with EPKSCS (SEQ ID NO: 1) terminus, P1AF4858, FIG. 20C) eliminates the reactivity with preexisting antibodies in plasma compared to a molecule OX40 (49B4) x FAP (1G1a) (2+1) with a free C-terminus EPKSC (SEQ ID NO: 6) (P1AE6840, FIG. 20A).
[0449] FIGS. 21A to 21H show a set of OX40 (MOXR0916) x FAP (1G1a) molecules with increasing C-terminal extensions. C-terminal extension of an aspartate (Molecule OX40 (MOXR0916) x FAP (1G1a) (2+1) with EPKSCD (SEQ ID NO: 3) terminus, P1AF4852, FIG. 21B) reduces the reactivity with preexisting antibodies in plasma compared to a molecule OX40 (MOXR619) x FAP (1G1a) (2+1) with a free C-terminus EPKSC (SEQ ID NO: 6) (P1AE8872, FIG. 21A), whereas slightly increased reactivity is observed for the C-terminus EPKSCDK (SEQ ID NO: 4) (molecule (MOXR619) x FAP (1G1a) (3+1), P1AF4846, FIG. 21C). High reactivity has been observed for the molecule with the C-terminus EPKSCDKT (SEQ ID NO: 164) (molecule (MOXR619) x FAP (1G1a) (3+1), P1AF4847, FIG. 21D). The reactivity is again reduced for the molecules with the C-terminus EPKSCDKTH (SEQ ID NO: 165) (molecule (MOXR619) x FAP (1G1a) (2+1), P1AF4855, FIG. 21E) and with the C-terminus EPKSCDKTHT (SEQ ID NO: 7) (molecule (MOXR619) x FAP (1G1a) (2+1), P1AF4856, FIG. 21F). Replacement of the C-terminal T with amino acid L, which is not naturally occurring at this position in the upper hinge region, completely eliminates the reactivity with preexisting antibodies in plasma (molecule (MOXR619) x FAP (1G1a) (2+1), P1AF4857, FIG. 21G), comparable with a C-terminal serine (molecule OX40 (MOXR0916) x FAP (1G1a) (2+1) with EPKSCS (SEQ ID NO: 1) terminus, P1AF4858, FIG. 21H). FIG. 22 summarizes the results.
What is the common sequence for CH1 for the (MOXR0916) x FAP (1G1a) prototype?
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The POSA could reasonably conclude in view of the limited working examples that the core cross-fab CH1 of the instant claimed invention comprises SEQ ID NO: 123 with a C-deletion and the extensions for one of SEQ ID NOs: 2. 4 and 5.
GITR x FAP (4B9) prototype
[0451] Furthermore, a set of GITR bispecific antigen binding molecules was also tested, i.e. the bispecific antigen binding molecule GITR x FAP (4B9) (2+1) and its C-terminal variants with EPKSCS (SEQ ID NO: 1) terminus (P1AG1036) and with EPKSCG (SEQ ID NO: 2) terminus (P1AG1039). The results are shown in FIGS. 24A to 24C. It confirms the previous results that a C-terminal extension of a serine (P1AG1036, FIG. 24B) eliminates the reactivity with preexisting antibodies in plasma compared to the respective molecule with a free C-terminus (P1AE1116, FIG. 24A). Similar to the serine extension variant, a further extension variant with a glycine, which is also not naturally located at this position of the upper hinge region, was generated. The glycine extension variant also eliminates the unwanted reactivity (P1AG1039, FIG. 24C).
What is the common sequence for CH1 for the GITR x FAP (4B9) prototype?
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144
782
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The POSA could reasonably conclude in view of the limited working examples that the core cross-fab CH1 of the instant claimed invention comprises SEQ ID NO: 120 with a C-deletion and the extensions for one of SEQ ID NOs: 2, 4 and 5.
The POSA could reasonably conclude that the core cross-fab CH1 for the inventive structures is similar if not identical for the CH1 portion of the cross-fab molecules used in the experimentation.
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Has Applicant provided a common structure sufficient to visualize the genus?
Applicant has provided a common structure for a common CH1 domain used in the experiments that is shared between the sequences of SEQ ID NOs 123 and 120 ands from which the instant claimed C-terminal extensions are performed and tested. Otherwise, there is no common structure for the instant claimed universe of C-terminal CH1-extended bispecific antibodies to ascribe for the reactivity toward preexisting anti-drug antibodies as reduced or non-reactive altogether (Surowka et al (PTO 892)).
The POSA could reasonably conclude that C-terminal extensions to a universal cross-fab CH1 domain have not been demonstrated by Applicants to place them in possession of the full scope of the invention.
Conclusion
12. No claims are allowed.
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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