DETAILED ACTION
Claims 48-52, 54-61, 67-75, and 77-89 are pending.
Election/Restrictions
Applicants’ species election without traverse in the reply filed on 01/26/2026 has been acknowledged. The following species have been elected:
Three specific heavy chain CDRs for CD137: SEQ ID NOs: 50, 51, and 52.
Three specific heavy chain CDRs for PD-L1: SEQ ID NOs: 68, 55, 56.
Three specific light chain CDRs: SEQ ID NOs: 111, 112, and 113.
Any applicable heavy chain or light chain full length sequences: SEQ ID NOs: 49, 67, and 110.
Upon further review and applicant’s response, in the reply filed on 01/26/2026, the restriction of claims 48-52, 54-61, 67-75, and 77-89 has been withdrawn.
Claims 48-52, 54-61, 67-75, and 77-89 are under examination.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 03/27/2023 has been considered by the examiner.
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.
Claims 59, 61, 79, 82, and 85 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.
The fundamental factual inquiry is whether the specification conveys with reasonable
clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of
the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at
1117.
The factors to be considered when analyzing claims for compliance with the written
description requirement include: actual reduction to practice; disclosure of drawings or structural
chemical formulas; sufficient relevant identifying characteristics (e.g., disclosure of complete or
partial structure, physical and/or chemical properties, structure/function correlation); method of
making the claimed invention; level of skill and knowledge in the art; and predictability in the art.
See MPEP §2163.
Claims 59, 61, 79, 82, and 85 recite “having at least 80%, 85%, 90%, 95%, or 99% sequence identity” to SEQ ID Nos: 49, 67, and 110. While the specification provides examples of SEQ ID Nos: 49, 67, and 110, it fails to disclose any species of antibodies that are 80-99% identical to the heavy chain sequences of claims 59, 61, 79, and 82, or the light chain sequence of claim 85. The specification does not provide any guidance regarding which specific residues of each VH or VL chain, can be varied while still maintaining binding specificity. The disclosed species are not sufficiently representative of the broad genus of different antibodies encompassed by the present claims. Claims 59, 61, 79, 82, and 85 are drawn to a method of using undefined structures. The Federal Circuit has clarified Written Description as it applies to antibodies in the recent decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AIA first paragraph) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of an antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
While generically the structure of antibodies is known, the structure of the presently
recited antibodies can vary substantially within the above given claimed recitations. As noted in
Amgen, knowledge that an antibody binds to a particular epitope on an antigen tells one nothing
at all about the structure of the antibody, wherein “instead of analogizing the antibody-antigen
relationship to a ‘key in a lock,’ it [is] more apt to analogize it to a lock and ‘a ring with a million
keys on it.” (Internal citations omitted). The relevant antibody art confirms this quandary,
indicating that “knowledge of an epitope or antigen used to generate a monoclonal antibody is
insufficient for making the original antibody available, even if suitable in vitro test systems for
screening are used.” See p. 8, lines 3-5 of WO 2009/033743 A1. Therefore, those of skill in the
art would not accept that the inventor had been in possession of the full genus of nanobodies
encompassed by the claims.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991), clearly states that
“applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date
sought, he or she was in possession of the invention. The invention is, for purposes of the
‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does
not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is
claimed.” (See Vas-Cath at page 1116).
The skilled artisan cannot envision the detailed chemical structure of the encompassed
claimed agents (if any), and therefore conception is not achieved until reduction to practice has
occurred, regardless of the complexity or simplicity of the method of identification. Adequate
written description requires more than a mere statement that it is part of the invention and
reference to a potential method of isolating it. The compound itself is required. See Fiers v.
Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co.
Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for
lack of written description support, especially in technology fields that are highly unpredictable,
where it is difficult to establish a correlation between structure and function for the whole genus
or to predict what would be covered by the functionally claimed genus. Abbvie Deutschland
GMBH & Co. v. Janssen Biotech, Inc. (759 F.3d 1285 (Fed. Cir. 2014). “When a patent claims a
genus using functional language to define a desired result, the specification must demonstrate
that the applicant has made a generic invention that achieves the claimed result and do so by
showing that the applicant has invented species sufficient to support a claim to the functionally-
defined genus." Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005).
Therefore, the full breadth of the claims does not meet the written description provision
of 35 U.S.C. §112, first paragraph. Applicants are reminded that Vas-Cath makes clear that the
written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see
page 1115).
Thus, claims 59, 61, 79, 82, and 85 are rejected under 35 USC 112(a) for failing to comply with the written description requirement.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 48-55, 67-74, 77, 87, and 89 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wallweber et al, (WO 2017/161030 A1) (IDS filed on 03/27/2023).
Instant claim 48 recites “A method for detecting and/or quantifying the presence in a sample of clustering of at least two cell surface moieties, comprising a first cell surface moiety and a second cell surface moiety, wherein the first and second cell surface moieties are expressed by different cells or different types of cells, and wherein the first and second cell surface moieties are not HER2 and HER2: HER1 and HER2: HER2 and HER3: HGF and c-Met; HER3 and PI3K: or PD-1 and PD- 1;the method comprising: contacting a sample in which the first and second cell surface moieties have been exposed to an agent having binding specificity for at least the first and second cell surface moieties with a first binding molecule that specifically binds to the first cell surface moiety and a second binding molecule that specifically binds to the second cell surface moiety, wherein at least one of the first binding molecule and the second binding molecule comprises a molecular tag which is not detected unless the first and second cell surface moieties are in proximity of each other; and detecting the presence or absence and/or measuring the amount of the molecular tag to detect and/or quantify the presence in the sample of clustering of the first cell surface moiety and the second”.
Wallweber teaches a method for detecting and/or quantifying the presence in a sample of clustering of at least two cell surface moieties (see claim 1 of Wallweber), comprising a first cell surface moiety and a second cell surface moiety, wherein the first and second cell surface moieties are expressed by different cells or different types of cells (see claims 13, 16, and 19 of Wallweber),
the method comprising: contacting a sample in which the first and second cell surface moieties have been exposed to an agent having binding specificity for at least the first and second cell surface moieties with a first binding molecule that specifically binds to the first cell surface moiety and a second binding molecule that specifically binds to the second cell surface moiety (see claim 1 of Wallweber),
wherein at least one of the first binding molecule and the second binding molecule comprises a molecular tag which is not detected unless the first and second cell surface moieties are in proximity of each other (see claim 1 of Wallweber); and
detecting the presence or absence and/or measuring the amount of the molecular tag to detect and/or quantify the presence in the sample of clustering of the first cell surface moiety and the second cell surface moiety (see claim 1 of Wallweber) (instant claims 48 and 67-78).
Wallweber teaches the method for determining the effectiveness of an agent, and confirming the mode of action of the agent (see [0097]) (instant claims 67-68), the sample being a tissue sample, a blood sample, a tumor biopsy, or cultured cells (see claims 5-8 of Wallweber) (instant claim 52), the first cell being expressed by immune effector cell CD137 (see [0038]) and the second cell being PD-L1 (see [0009], see [0038]) (instant claims 54-55, 70, 74, 77, and 87).
Wallweber teaches wherein the first and second cell surface moieties are not HER2 and HER2; HER1 and HER2; HER2 and HER3; HGF and c-Met; HER3 and PI3K; or PD-1 and PD-L1 (see [0038] “In another example, the first protein may be CD28 or CTLA4 and the second protein may be CD80 or CD86. In another example, the first protein may be BTLA4 and the second protein may be HVEM. In another example, the first protein may be TIM3 and the second protein may be GAL9. In another example, the first protein may be CD27 and the second protein may be CD70. In another example, the first protein may be CD40L and the second protein may be CD40. In another example, the first protein may be CD 137 and the second protein may be CD137L. In another example, the first protein may be OX40 and the second protein may be OX40L. In another example, the first protein may be ICOS and the second protein may be B7RP1. In another example, the first protein may be GITR and the second protein may be CITRL. In some instances, the first cell may be a T cell and the first protein may be PD-1, CTLA4, BTLA4, TIM3, CD27, CD28, CD40L, CD137, OX40, ICOS, or GITR. In some instances, the second cell may be a tumor cell and the second protein may be PD-L1, PD-L2, CD80, CD86, HVEM, GAL9, CD70, CD40, CD137L, OX40L, B7RP1, or GITRL”) (instant claims 48, 67-68, 71-72, and 89).
Wallweber teaches a method for treating a subject in need thereof, in particular a subject having cancer, the method comprising: treating a subject with an agent binding a first cell surface moiety and a second cell surface moiety (see [0097] teaching treating a subject with a first cell surface moiety and a second cell surface moiety, see [0032]);
analyzing the effectiveness of the agent or the mode of action of the agent (see [0011] teaching a method of screening test agents for the ability to disrupt or promote formation of a protein-protein interaction); and
continuing or adapting the treatment based on the outcome of the analysis or confirmation (see [0032], see [0097]) (instant claims 71 and 89).
Wallweber teaches a) contacting the sample with a first binding molecule that specifically binds to the first cell surface moiety and a second binding molecule that specifically binds to the second cell surface moiety, wherein the first binding molecule comprises a molecular tag attached thereto via a cleavable linker and the second binding molecule comprises a cleavage inducing moiety (see [0003]); or
b) contacting the sample with a first binding molecule that specifically binds to the first cell surface moiety and a second binding molecule that specifically binds to the second cell surface moiety, wherein the second binding molecule comprises a molecular tag attached thereto via a cleavable linker and the first binding molecule comprises a cleavage inducing moiety (see [0005]);
- inducing cleavage of the molecular tag (see [0005]); and
- detecting the presence or absence, or measuring the amount, of released molecular tag thereby detecting or quantifying clustering of the first cell surface moiety with the second cell surface moiety in the sample (see [0005]) (instant claim 49). Willweber also teaches the use of a third binding molecule (see [0005]) (instant claim 50), and a fourth binding molecule (see [0006]) (instant claim 51).
Wallweber teaches the mode of action is the simultaneous binding of the agent to the first and second cell surface moiety (see [0003] teaching the binding of the first and second cell surface moiety happening in one step (step b)) (instant claim 69). Wallweber teaches contacting one or more test cell cultures with a test agent (see [0011], see claims 1 and 5 of Wallweber), wherein the test cell culture comprises a cell expressing a first cell surface moiety, and a cell expressing a second cell surface moiety (see claim 1 of Wallweber); detecting or quantifying the level of clustering of the first and second cell surface moieties (see [0011], see claim 1 of Wallweber) and comparing the level of clustering with the level of clustering detected for the clustering in a control cell culture not contacted with the test agent or contacted with a reference agent, wherein the control cell culture comprises the first surface moiety, and the second cell surface moiety (see [0011], see [0012]) (instant claim 71), and selecting a test agent that induces an equal or higher level of clustering than the level of clustering in the control cell culture (see [0009], see claim 12 of Wallweber) (instant claim 73).
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.
Claims 56-57, 75, and 88 are rejected under 35 U.S.C. 103 as being unpatentable over Wallweber et al, as applied to claims 48-55, 67-74, 77, 87, and 89 above, in view of Altintas et al., (WO 2019/025545 A1) (IDS filed on 03/27/2023).
The teachings of Wallweber as it pertains to claims 48-55, 67-74, 77, 87, and 89 are discussed int eh 35 USC 102 rejection above.
Wallweber does not teach a bispecific antibody that binds to CD137 or another immune effector cell co- stimulatory molecule and PD-L1 or another tumor-associated moiety or immune checkpoint moiety.
Altintas teaches a bispecific antibody that binds to CD137 or another immune effector cell co- stimulatory molecule and PD-L1 or another tumor-associated moiety or immune checkpoint moiety (see claim 1 of Altintas, see page 1 lines 3-5 “The present invention relates to novel binding agents and their use in medicine. In particular, the invention relates to binding agents, such as bispecific antibodies, binding human PD-L1 and binding human CD137.”, see page 2 lines 30-35) (instant claims 56-57, 75, and 88).
It would have been obvious to one of ordinary skill in the art at the time of the instant application to modify the methods of detecting and/or quantifying a protein-protein interaction between two cells in a sample of Wallweber with the bispecific antibody taught by Altintas. Altintas provides motivation by teaching that the PD-L1 and CD137 binding agents are particularly useful in therapeutic settings where stimulation of an activation receptor such as CD137 and blocking of an inhibition signal such as PD-L1 on T cells can be achieved simultaneously, which results in a higher magnitude of T cell proliferation, activation and survival than the agents being used separately (see page 4 lines 3-7). The artisan would have reasonable expectation of success based on the cumulative disclosure of these prior art references at the time the instant application was filed.
Claim 86 is rejected under 35 U.S.C. 103 as being unpatentable over Wallweber and Altintas et al., as applied to claims 56-57, 75, and 88 above, in view of Bakker et al., (US9914777B2) (effectively filed on 07/08/2016).
The teachings of Wallweber and Atlintas as it pertains to claims 56-57, 75, and 88 are discussed in the 35 USC 103 rejection above.
Wallweber does not teach SEQ ID NO: 110.
Bakker teaches a method of treating cancer in a subject comprising administering a bispecific antibody which comprises a light chain variable region with SEQ ID NO:110 (see claims 1 and 8 of Bakker. Instant SEQ ID NO: 110 is identical to SEQ ID NO: 16 of Bakker) (instant claim 86).
It would have been obvious to one of ordinary skill in the art at the time of the instant application to modify the methods of detecting and/or quantifying a protein-protein interaction between two cells in a sample of Wallweber with the light chain variable region taught by Bakker. Bakker provides motivation by teaching the use of SEQ ID NO: 16 (Instant SEQ ID NO: 110 is identical to SEQ ID NO: 16 of Bakker) has been successfully and routinely used in the art before the instant application (see column 19). The artisan would have reasonable expectation of success based on the cumulative disclosure of these prior art references at the time the instant application was filed.
Allowable Subject Matter
Claims 58, 60, 78, 80, 81, and 83-84 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claims 58, 60, 78, 80, 81, and 83-84 are allowable because it is not found in the prior art a teaching or suggestion of a binding domain of the bispecific antibody that binds to CD137 comprising a heavy chain CDR1 with the amino acid SEQ ID NO: 50; and a heavy chain CDR2 with the amino acid SEQ ID NO: 51; and a heavy chain CDR3 with the amino acid SEQ ID NO: 52.
It is not found in the prior art a teaching or suggestion of a binding domain of the bispecific antibody that binds to PD-L1 comprising a heavy chain CDR1 with the amino acid SEQ ID NO: 68; and a heavy chain CDR2 with the amino acid SEQ ID NO: 55; and a heavy chain CDR3 with the amino acid SEQ ID NO: 56.
It is not found in the prior art a teaching or suggestion of the binding domain of the bispecific antibody that binds to CD137 comprising a heavy chain variable region having SEQ ID NO: 49.
It is not found in the prior art a teaching or suggestion of the binding domain of the bispecific antibody that binds to PD-L1 comprises a heavy chain variable region having SEQ ID NO: 67.
It is not found in the prior art a teaching or suggestion of a binding domain of the bispecific antibody that binds to CD137 and PD-L1 comprising a light chain variable region CDR1 having SEQ ID NO: 111, a light chain CDR2 with amino acid SEQ ID NO: 112, and a light chain CDR3 with amino acid SEQ ID NO: 113.
The closest prior art reference to claims 58, 60, 78, 80, 81, and 83-84 is Wallweber et al, (WO 2017/161030 A1) (IDS filed on 03/27/2023).
Wallweber teaches a method for detecting and/or quantifying the presence in a sample of clustering of at least two cell surface moieties, comprising a first cell surface moiety and a second cell surface moiety, wherein the first and second cell surface moieties are expressed by different cells or different types of cells, and wherein the first and second cell surface moieties are not HER2 and HER2: HER1 and HER2: HER2 and HER3: HGF and c-Met; HER3 and PI3K: or PD-1 and PD- 1;the method comprising: contacting a sample in which the first and second cell surface moieties have been exposed to an agent having binding specificity for at least the first and second cell surface moieties with a first binding molecule that specifically binds to the first cell surface moiety and a second binding molecule that specifically binds to the second cell surface moiety, wherein at least one of the first binding molecule and the second binding molecule comprises a molecular tag which is not detected unless the first and second cell surface moieties are in proximity of each other; and detecting the presence or absence and/or measuring the amount of the molecular tag to detect and/or quantify the presence in the sample of clustering of the first cell surface moiety and the second.
Wallweber does not teach or suggest a binding domain of the bispecific antibody that binds to CD137 that comprises SEQ ID NOs: 50, 51,52, and 49. Wallweber does not teach or suggest a binding domain of the bispecific antibody that binds to PD-L1 comprising SEQ ID NOs: 68, 55, 56, and 67. Wallweber does not teach or suggest a bispecific antibody that binds to CD137 and PD-L1 that comprises SEQ ID NOs: 111, 112, and 113.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MCKENZIE A DUNN whose telephone number is (571)270-0490. The examiner can normally be reached Monday-Tuesday 730 am -530pm, Wednesday-Friday 730 am-430 pm.
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/MCKENZIE A DUNN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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