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 reply filed on 8/4/2026 is acknowledged. Claims 4, 17, 20, 23, 26-30, 33, 35, 36, 38, 45, 47-52 and 61 are pending. Claims 1-3, 5-16, 18-19, 21-22, 24-25, 31-32, 34, 37, 39-44, 46, 53-60 and 62 are canceled. Claims 20, 33, 36 and 48-52 are withdrawn. Claims 26-28, 30 and 45 are amended.
3. Claims 4, 17, 23, 26-30, 35, 38, 45, 47 and 61 are under examination.
4. In the reply filed on 12/8/2025, applicant elected the following species:
(i) the antibody corresponding to item m) of claim 4 (wherein the VH comprises the HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 123, and the VL comprises the LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 124, the LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 125, and the LC -CDR3 comprising the amino acid sequence of SEQ ID NO: 126) and
(ii) IgG4 Fc
Objections and Rejections Withdrawn
5. All objections and rejections except those maintained below are withdrawn in view of applicant’s amendments.
Rejections Maintained
Improper Markush Grouping Rejection
6. Claims 4, 23, 26-30, 35, 38, 45, 47 and 61 remain rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
MPEP 2117 states “Claims that set forth a list of alternatives from which a selection is to be made are typically referred to as Markush claims, after the appellant in Ex parte Markush, 1925 Dec. Comm’r Pat. 126, 127 (1924). Although the term “Markush claim” is used throughout the MPEP, any claim that recites alternatively usable members, regardless of format, should be treated as a Markush claim.”.
A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 706.03(y).
The Markush grouping of the claims is improper because the alternatives defined by the Markush grouping (i.e. antibodies comprising different 6 CDR sequences) are not disclosed in the specification or known in the art to be functionally equivalent and have a common use. Antibodies comprising different 6 CDRs are not functional equivalent because they bind to different epitopes. Antibodies with different CDRs have different sequences, result in different structures, and bind to different epitopes, as such are not functionally equivalent. Antibodies that bind to different epitopes will induce different in vivo responses. Antibodies that bind to a certain epitope of a protein may act as antagonist of that protein, while antibodies that bind to other epitopes of that same protein may act as agonists of that protein, and even further, antibodies that bind to certain other epitopes of that same protein may not induce any effect at all. Zabel et al. (US 2023/0340123A1, pub. date: 10/26/2023) discloses that anti-BTLA antibodies 16-I20A, 15-C19A and 16-H16A augmented SEB-induced IL-2 secretion by T cells, and thus served as BTLA antagonists; anti-BTLA antibodies 12-18A, 8-M23A and 13-F7A suppressed SEB-induced IL-2 secretion by T cells, and thus served as BTLA agonists (Example 5). As such, antibodies that have different VH CDRs and VL CDRs which bind to different epitopes would give rise to different in vivo responses, and may not be regarded as functionally equivalent. Furthermore, they do not share both a substantial structural feature and a common use that flows from the substantial structural feature. While the term “antibody” does impart some structure, the structure that is common to antibodies is generally unrelated to antigen-binding function. The 6 CDRs are generally considered to be the region of contact between the antibody and the antigen.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Applicant’s Arguments
The response states that 1) the anti-CD73 antibody moieties recited in the claims are all polypeptides having at least one common property, and 2) as explained in the Decision on Appeal in Ex parte Malcolm Andrew Ward, Abdul Hye, Simon Harold Lovestone, and Richard James Butler Dobson, Appeal No. 2021- 003776, dated June 10, 2022 ("Ex parte Ward," a copy of which is attached hereto), polypeptides having at least one common property are a proper Markush grouping. The Board referred to M.P.E.P. § 2117(II)(A), last paragraph, which states:
[A] Markush grouping is ordinarily proper if all the members of the group
belong to a recognized class (whether physical, chemical, or art
recognized) and are disclosed in the specification to possess at least one
property in common which is mainly responsible for their function in the
claimed invention, and it is clear from their very nature or from the prior art
that all members possess this property.
The Board noted that "the Examiner acknowledge[d] that the ten biomarkers are polypeptides, a recognized chemical class." Ex parte Ward at 4 (emphasis added). The Board also determined that Appellant's specification "provide[d] sufficient evidence ... showing that the recited biomarker polypeptides 'possess at least one property in common which is mainly responsible for their function in the claimed invention."' Id. at 4.
Applicant respectfully submits that, here, the antibody moieties recited in the pending claims are-like the biomarkers recited in claim 56 in Ex parte Ward- polypeptides, a recognized chemical class, as evidenced by (at least) their amino acid sequences. Furthermore-and also like the biomarkers recited in claim 56 in Exparte Ward-the antibodies recited in the pending claims possess at least one property in common which is (at least) "mainly responsible for their function in the claimed invention" (Ex parte Ward at 4). For example, the instant specification discloses that the recited antibody moieties possess the property of binding to CD73. Example 1 discusses, for example, the preparation of anti-CD73 antibodies and variants including Clone # 3, 9, 23, 25, 33, 35, 5, 6, 17, 18, 19, 20, 2-9, 2-9-1, 2-9-2, and 2-11. Additionally, Example 2 discusses, for example, the CD73 binding ability of selected antibodies, including Clone # 2-9 IgG2, 2-9-1 IgG1 SELF, and 2-9-2 IgG4. Moreover, because it is well-known in the art that the CDRs of an antibody define its binding specificity, one skilled in the art would reasonably expect the claimed antibodies containing the CDRs of the exemplary antibodies to share the same common property-
of binding to CD73.
Because the antibodies of the pending claims are within the recognized chemical class of polypeptides and possess at least one common property of binding to CD73, the Markush grouping of the claimed antibody moieties is proper under M.P.E.P. § 2117(ll)(A).
Response to Arguments
Applicant’s arguments have been carefully considered but are not persuasive. The Board decision on Appeal in Ex parte Malcolm Andrew Ward, Abdul Hye, Simon Harold Lovestone, and Richard James Butler Dobson, Appeal No. 2021- 003776, dated June 10, 2022 does not apply to instant claims. Appellant’s claims are directed to a set of well recognized proteins. Appellant’s specification discloses that these proteins have a common use (they are markers for a neurocognitive disorder). Furthermore, the Board decision is nonprecedential.
In the instant case, the Markush grouping of the claims is improper because the alternatives defined by the Markush grouping (i.e. antibodies comprising different 6 CDR sequences) are not well recognized proteins (e.g. the elected antibody is novel) and are not disclosed in the specification or known in the art to be functionally equivalent and have a common use. As indicated in the previous office action, antibodies comprising different 6 CDRs are not functional equivalent because they bind to different epitopes. Antibodies that bind to different epitopes induce different in vivo responses. Antibodies that bind to a certain epitope of a protein may act as antagonist of that protein, while antibodies that bind to other epitopes of that same protein may act as agonists of that protein, and even further, antibodies that bind to certain other epitopes of that same protein may not induce any effect at all. Zabel et al. (US 2023/0340123A1, pub. date: 10/26/2023) discloses that anti-BTLA antibodies 16-I20A, 15-C19A and 16-H16A augmented SEB-induced IL-2 secretion by T cells, and thus served as BTLA antagonists; anti-BTLA antibodies 12-18A, 8-M23A and 13-F7A suppressed SEB-induced IL-2 secretion by T cells, and thus served as BTLA agonists (Example 5). As such, antibodies that have different VH CDRs and VL CDRs which bind to different epitopes would give rise to different in vivo responses, and may not be regarded as functionally equivalent. Furthermore, they do not share both a substantial structural feature and a common use that flows from the substantial structural feature. While the term “antibody” does impart some structure, the structure that is common to antibodies is generally unrelated to antigen-binding function. The 6 CDRs are generally considered to be the region of contact between the antibody and the antigen.
For the foregoing reasons, the rejection is deemed proper and is therefore maintained.
Double Patenting
7. 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.
8. Claims 4, 17, 23, 26-30, 35, 38, 45, 47 and 61 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1,18, 21, 24, 27, 30, 47, 50-54, 60, 64-66, 68-69, 84, 86-91 and 102 of copending Application No. 17/822,737 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1,18, 21, 24, 27, 30, 47, 50-54, 60, 64-66, 68-69, 84, 86-91 and 102 of the copending Application No. 17/822,737 (reference application) disclose a multispecific antibody that binds to human CD137 and human EGFR, comprising a first antibody moiety that binds to human CD137 and a second antibody moiety that binds to human EGFR, wherein the first antibody moiety comprises a heavy chain variable region (VH) comprising amino acids having the sequence set forth in SEQ ID NO: 127 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 128, wherein the first antibody moiety is a human CD137 agonist antibody, wherein the first antibody moiety comprises an antibody or antigen-binding fragment thereof selected from the group consisting of a full-length antibody, a multispecific antibody a scFv, a Fab fragment, a Fab' fragment, a F(ab')2, and a scFv-Fc fusion, the Fc region comprises an IgG4 Fc region, and the IgG4 Fc region comprises a S228P mutation. The claims further disclose an immunoconjugate comprising the multispecific antibody, linked to a therapeutic agent or a label, a pharmaceutical composition comprising the multispecific antibody, and a pharmaceutically acceptable carrier, and a kit comprising the multispecific antibody. The amino acid sequences of SEQ ID NOs: 127 and 128 are 100% identical to instant SEQ ID NOs: 127 and 128, respectively (see sequence alignments below). SEQ ID NO: 127 comprises instant SEQ ID NOs: 121-123. SEQ ID NO: 128 comprises instant SEQ ID NO: 124-126.
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9. Claims 4, 17, 23, 26-30, 35, 38, 45, 47 and 61 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4, 18, 21, 24, 27, 30, 49-54, 57, 59-61, 63-64, 76-82 and 94 of copending Application No. 17/822,750 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 4, 18, 21, 24, 27, 30, 49-54, 57, 59-61, 63-64, 76-82 and 94 of copending Application No. 17/822,750 (reference application) disclose a multispecific antibody that binds to CD137 and HER2, comprising a first antibody moiety that binds to CD137 and a second antibody moiety that binds to HER2, wherein the first antibody moiety comprises a heavy chain variable region (VH) comprising amino acids having the sequence set forth in SEQ ID NO: 127 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 128, wherein the first antibody moiety is a human CD137 agonist antibody, wherein the first antibody moiety comprises an antibody or antigen-binding fragment thereof selected from the group consisting of a full-length antibody, a multispecific antibody a scFv, a Fab fragment, a Fab' fragment, a F(ab')2, and a scFv-Fc fusion, the Fc region comprises an IgG4 Fc region, and the IgG4 Fc region comprises a S228P mutation. The claims further disclose an immunoconjugate comprising the multispecific antibody, linked to a therapeutic agent or a label, a pharmaceutical composition comprising the multispecific antibody, and a pharmaceutically acceptable carrier, and a kit comprising the multispecific antibody. The amino acid sequences of SEQ ID NOs: 127 and 128 are 100% identical to instant SEQ ID NOs: 127 and 128, respectively (see sequence alignments below). SEQ ID NO: 127 comprises instant SEQ ID NOs: 121-123. SEQ ID NO: 128 comprises instant SEQ ID NO: 124-126.
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Applicant’s Arguments
The response states that the claims of co-pending U.S. Application No. 17/822,750 and co-pending U.S. Application No. 17/822,737 do not teach or suggest all limitations of claim 4. In particular, the claims of U.S. Application No. 17/822,750 relate to an anti- CD137 x anti-HER2 multispecific antibody, and the claims of U.S. Application No. 17/822,737 relate to an anti-CD137 x anti-EGFR multispecific antibody. Neither the claims of U.S. Application No. 17/822,750 nor the claims of U.S. Application No. 17/822,737 teach or suggest the isolated anti-CD137 construct of the present application. Accordingly, Applicant respectfully submits that there is no issue of nonstatutory double patenting regarding claim 4 (or claims 17, 23, 26-30, 35, 38, 45, 47, and 61 by virtue of dependency) with respect to the claims of co-pending U.S. Application No. 17/822,750 or the claims of co-pending U.S. Application No. 17/822,737.
Response to Arguments
Applicant’s arguments have been carefully considered but are not persuasive. Instant claim 4 recites “An isolated anti-CD137 construct comprising an anti-CD137 antibody moiety…”. The term “comprising” is open, as such it does not preclude the construct to comprise a second and a third antibody moiety. This is further evidenced by claim 26. Claim 26 is drawn to the isolated anti-CD137 construct of claim 4, wherein the construct further comprises a full-length antibody, a multispecific antibody, a single-chain Fv (scFv), a Fab fragment, a Fab' fragment, a F(ab')2, an Fv fragment, a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, a VHH, a Fv-Fc fusion, a scFv-Fc fusion, a scFv-Fv fusion, a diabody, a tribody, or a tetrabody.
New Grounds of Rejection
Claim Rejections - 35 USC § 112
10. 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.
11. Claim 26 is 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. This is a new matter rejection.
Claim 26 is amended to recite a limitation “wherein the construct further comprises a full-length antibody, a multispecific antibody, a single-chain Fv (scFv), a Fab fragment, a Fab' fragment, a F(ab')2, an Fv fragment, a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, a VHH, a Fv-Fc fusion, a scFv-Fc fusion, a scFv-Fv fusion, a diabody, a tribody, or a tetrabody”. The amendment introduces new matter since the specification, drawings and claims as filed does not provide clear support for this limitation. For example, the specification does not disclose a construct comprising an anti-CD137 antibody moiety and a multispecific antibody. The specification discloses a construct which is a multispecific antibody which comprises an anti-CD137 antibody moiety, and a second antibody moiety (page 17, lines 27-32).
If applicant believes that support for the above-mentioned phrases or terms is present in the specification, claims or drawing as originally filed, applicant must, in responding to this action, point out with particularity, where such support may be found.
Applicant is required to cancel the new matter in the reply to this Office Action.
Conclusion
12. No claims are allowed.
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 HONG SANG whose telephone number is (571)272-8145. The examiner can normally be reached Monday-Friday 8am-5pm.
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, Gregory Emch can be reached at 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/HONG SANG/Primary Examiner, Art Unit 1646
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