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
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 1/28/2026 has been entered.
Claims 1, 5-18, 23-27, and 30-31 are now pending. Claims 1, 12, and 15 are amended. Claims 23-27 remain withdrawn.
Claims 1, 5-18, and 30-31 are currently being examined.
Maintained Rejection
(Arguments and Amendments addressed)
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.
Claimsremain 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 WRITTEN DESCRIPTION rejection.
The claims are drawn to a therapeutic composition comprising a multivalent antibody comprising a first variable domain that binds a first tumor antigen (TA1), a second variable domain that binds a second tumor antigen (TA2), and a third variable domain that binds an immune cell engaging antigen (IEA); and an Fc region, and wherein the composition further comprises a second binding molecule that binds TA1 or TA2, and wherein the second binding molecule competes with the multivalent antibody for binding to TA1 or TA2; and wherein the third variable domain that binds to an immune cell engaging antigen (IEA) and the second variable domain that binds to TA2 are associated with an Fc region, and the first variable domain that binds to a TA1 is linked to the third variable domain that binds to IEA; or wherein the third variable domain that binds an IEA and he first variable domain that binds to a TA1 are associated with an Fc region, and the second variable domain that binds a TA2 is linked to the third variable domain that binds an IEA.
No structure of the multivalent antibody, or sequences of the first, second or third variable domains, or the second binding molecule is recited. Dependent claims 6-8 recite the targets of the variable domains.
The instant specification discloses the following: (1) sequences of the CD3 variable domain [0080-0085], (2) sequences of the PD-L1 [0097-0105], (3) sequences of EGFR 0112-0117] No other structure of sequence of any other tumor antigen or immune cell engaging antigen is disclosed in the specification.
By the time of the filing of the instant application, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). Humanized antibodies comprise only the CDRs, or in some cases an abbreviated subset of residues within the CDRs, of a parental rodent antibody in the context of human framework sequences. Id. at Section 4. All of the CDRs of the heavy and light chain, in their proper order of CDR1, then 2, then 3, and in the context of framework sequences which maintain their required conformation are generally required to produce a humanized antibody in which the heavy and light chains associate to form an antigen-binding region that binds the same antigen as the parental rodent antibody. Id. at Section 4.
Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures, even when the antibodies are limited to those from a particular source (Gershoni et al., Epitope Mapping, Biodrugs 2007; 21 (3): 145-156 page 146 section 1.1). The skilled artisan therefore understood that antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites, particularly in the amino acid sequence and length of VH-CDR3.
Further, it is not possible to predict the amino acid sequence when an epitope is recited, because there are many different epitope arrangements, such as linear and discontinuous epitopes that is dictated by the unique interaction between an antibody and its cognate epitope (Blythe et al., Benchmarking B cell epitope prediction: Underperformance of existing methods, Protein Science (2005), 14:246–248 pg. 246) . 3D structural analyses of antibody-epitope binding highlighting that the deficiency in the ability to predict the structural features of an antibody when the epitope is disclosed (Schreiber et al.,3D-Epitope-Explorer (3DEX): Localization of Conformational Epitopes within Three-Dimensional Structures of Proteins, Wiley Interscience, 2005 42–44, 60596, page 879).
The structure activity relationship of the CDR antigen binding region that binds to any tumor antigen or any immune cell engaging domain is not known and the binding epitopes cannot be predicted based on the antibody sequences.
To provide adequate written description and evidence of possession of the claimed composition antibody genus, the instant specification can structurally describe representative multivalent antibodies or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.).
Although Applicants may argue that it is possible to screen for antibodies that function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future antibodies yet to be discovered that may function as claimed.
Given the lack of representative examples to support the full scope of the claimed antibodies, and lack of reasonable structure-function correlation with regards to the unknown sequences in the variable domains or CDRs of the antibodies that function as claimed, the present claims lack adequate written description.
Response to Arguments
Applicant argues that a person of ordinary skill in the art, reading the specification as a whole, would understand that the claimed invention is not limited to any specific structure or identity of TA1, TA2 or the immune effector antigen (IEA) binding domain. Applicant argues that the claimed invention does not reside in the particular identity of the TA1-binding, TA2 binding or IEA-binding domains. Rather, the invention resides in a therapeutic composition comprising a multivalent antibody and a competing second binding molecule, wherein the second binding molecule competes with the multivalent antibody for binding to TA1 or TA2 in order to modulate immune cell engaging activity and preferentially target tumor cells expressing both TA1 and TA2. Applicant argues that the specification discloses that TA1 and TA2 can be any antigen expressed on a tumor cell, and provides examples of these antigens, such as PDL1 x CD3 x EGFR, illustrating – but not limiting – the scope of the invention.
Applicants’ arguments have been considered but are not persuasive. The claims are drawn to a therapeutic composition comprising a multivalent antibody and a second binding molecule. The claims recite that the multivalent antibody has three variable domains that bind to a first tumor antigen, a second tumor antigen, and an immune cell engaging antigen. No structure of the multivalent antibody or the second binding molecule that binds to either a first or second tumor antigen is recited. The structure activity relationship of the CDR antigen binding region that binds to any tumor antigen or any immune cell engaging domain is not known. The structure of the antibody is necessary in order to determine the function of the antibody as recited in the 112(a) rejection above. The Applicant has not described a reasonable number of members of the genus of the multivalent antibodies and a second binding molecule that is required to function as claimed. Although the Applicant provides some examples of the specification, it would not permit a skilled artisan to visualize a genus of multivalent antibodies as claimed.
Maintained Rejection
(Amendments Addressed)
Claim Rejections - 35 USC § 103
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.
Claim(s) 1, 5-7, 9-13, 14-18, 30 and 31 remain rejected under 35 U.S.C. 103 as being unpatentable over Granda et al (WO2019195535A1; Published 10/10/2019; cited in IDS 7/29/2022), in view of Stuhler et al (US20150079093 A1; Published 3/19/2015) and Finnefrock et al (US20110008369A1; Published 1/13/2011).
Granda teaches that multispecific binding molecules engage at least two tumor associated antigens, in addition to a TCR complex, such as CD3. Granda teaches a therapeutic composition comprising a multivalent antibody: (1) Antigen-binding module 1 – that binds to a tumor associated antigen (TAA1), (2) Antigen binding module 2 - that binds to a tumor associated antigen (TAA2), and (3) An antigen binding module 3 that binds to a human T – cell receptor (TCR), which is CD3. [0006-0009] Granda second binding molecule; such as an immune cell antibody. [0806, 0863, 0864, 0867-0869] Granda teaches that additional agent may be administered simultaneously or consecutively. [0863] Granda teaches that the multivalent antibody comprises an Fc region. [0129-0131] Granda teaches that the therapeutic composition of claim 1, wherein the third variable domain and the second variable domain are associated with an Fc region, and the first variable domain is linked to the third variable domain. [see figure 2]
Regarding clam 5, Granda teaches that the first, second, and/or third variable domain comprises a common light chain variable region. [0109] Regarding claims 6 and 7, Granda teaches that the variable domain that binds to the immune cell engaging antigen binds to CD3, and that the variable domain that binds to TAA1 or TAA2, may be PD-L1. [0318-0319; 0329, 0345] Regarding claim 9, Granda teaches that the first tumor associated antigen is expressed on non-tumor cells. [0088, 0327] Regarding claim 18, Granda teaches that the multivalent antibody can be formulated as a pharmaceutical composition that comprises a pharmaceutically acceptable excipient or carrier. [0791-0793] Regarding claim 30, Granda teaches a vector comprising a nucleic acid encoding the heavy chain variable region of the first, second and third variable region of the multivalent antibody [0081, 0693] Regarding claim 31, Granda teaches a host cell comprising a nucleic acid encoding the heavy chain variable region of the first, second and third variable domain of the multivalent antibody. [0052, 00692-0701]
It is noted that textural instructions are viewed as a recitation of intended use and therefore do not differentiate the claims from the prior art (see MPEP 2112.01). Claims 15-17 reads on the instructions for administering the multivalent antibody and/or the second binding molecule.
However, Granda does not teach the following that the additional agent is a second binding molecule that binds to TA1 or TA2 and competes with the multivalent antibody.
Stuhler teaches a set of polypeptides that comprise the following: (1) a first polypeptide that binds to antigen "A1", (2) a second polypeptide binds to target "A2", and (3) a functional domain. Stuhler teaches that these antigens "A1" and "A2" are different from one another, and that the targeting moiety that targets the antigen are variable domains. [0033-0034, 0105, 0126, 0220] Stuhler teaches that it would be advantageous to target cells that simultaneously express a combination of antigens [0012] Stuhler exemplifies that these polypeptides in competitive blocking experiments as shown in Figures 6 and 7. Stuhler teaches that the functional domain is a T-cell engaging domain that specifically binds to CD3. [0186] Stuhler teaches that antigen 1 “A1” is EGFR. [0163] Stuhler teaches that antigen A1 and/or antigen A2 are expressed on surface of cells of a tumor on precursor cells, or expressed on non-tumor cells. [0103-0104, 0156]
Finnefrock teaches a binding molecule that binds to PD-L1. [Abstract] Finnefrock teaches that the PD-1 binding protein is a bispecific antibody, with reduced effector function. [0085] Finnefrock teaches that the binding protein may be part of a kit. [00222] Finnefrock teaches that administration of the binding protein can be alone or in combination with other agents, that includes a pharmaceutically acceptable carrier. [0187, 0191, 0200, 0220]
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to include a second binding molecule that binds to a tumor antigen that competes with the multivalent antibody for binding to TA1 or TA2 in the composition of Granda. One would have been motivated to, and have a reasonable expectation of success, because: (1) Granda teaches that multispecific binding molecules engage at least two tumor associated antigens, in addition to a TCR complex, such as CD3 and Granda second binding molecule; such as an immune cell antibody, which may be administered simultaneously or consecutively; (2) Stuhler teaches a set of polypeptides that comprise the following: (1) a first polypeptide that binds to antigen "A1", (2) a second polypeptide binds to target "A2", and (3) a functional domain, (3) Stuhler teaches that these antigens "A1" and "A2" are different from one another, that the targeting moiety that targets the antigen are variable domains, and exemplifies the competitive binding effects of these agents, (3) Finnefrock teaches a binding molecule that binds to PD-L1, and teaches that this agent may be combined with other agents.
Given the known methods of constructing a multivalent antibody comprising first and second variable domains that bind to tumor antigens, and a third variable domain that binds to an immune cell engaging agent, given the known methods of combining this antibody with a second antibody or binding molecule as taught by Granda, and given the known methods of other binding molecules that target tumor antigens and known mechanisms of competitive binding to the same antigen, one of skilled in the art could have pursued adding the second binding molecule that targets a tumor associated antigen to the multivalent antibody of Granda, with a reasonable expectation of success.
It is noted that claims 14-17 require a kit of parts comprising the multivalent antibody and the second binding molecule. One would have been motivated to, and have a reasonable expectation of success, because: (1) Granda teaches that multispecific binding molecules engage at least two tumor associated antigens, in addition to a TCR complex, such as CD3 and Granda second binding molecule; such as an immune cell antibody, which may be administered simultaneously or consecutively; and (2) Finnefrock teaches a binding molecule that binds to PD-L1 that may be included in a kit, and teaches that the binding molecule can be administered with other agents. Given the known uses of kits, and given the known use of other agents comprised in a kit, one of skill in the art could have put together a kit with the claimed therapeutic composition, with a reasonable expectation of success.
Claim(s) 8 remain rejected under 35 U.S.C. 103 as being unpatentable over Granda et al (WO2019195535A1; Published 10/10/2019), Stuhler et al (US20150079093 A1; Published 3/19/2015), and Finnefrock et al (US20110008369A1; Published 1/13/2011), as applied to claims 1, 5-7, 9-18, 30 and 31 above, and further in view of Wang et al (US20210403575 A1; filing date 10/22/2019).
The teachings of Granda, Stuhler, and Finnefrock are recited above. However, they do not teach that TA2 binds to EGFR (claim 8).
Wang teaches a bispecific antibody that binds to EGFR and PD-L1. [0006-0007, 0028, 0029, 0047] Wang teaches that this agent can be used as monotherapy or can be combined with other agents. [0012] Wang teaches that the bispecific antibody that targets two different antigens can build a bridge between a target cell and functional molecule and stimulates an immune response having guidance property. [0009]
It is noted that claim 8 requires that the variable domain that binds to TA2 binds to EGFR. One would have been motivated to, and have a reasonable expectation of success, because: (1) Granda teaches that multispecific binding molecules engage at least two tumor associated antigens, in addition to a TCR complex, such as CD3 and Granda second binding molecule; such as an immune cell antibody, which may be administered simultaneously or consecutively; (2) Stuhler teaches a set of polypeptides that comprise the following: (1) a first polypeptide that binds to antigen "A1", (2) a second polypeptide binds to target "A2", and (3) a functional domain, (3) Stuhler teaches that the antigen targets may include EGFR, and (4) Wang teaches a bispecific agent that targets both EGFR and PD-L1 and teaches the known benefits of targeting these two tumor antigens. Given the known agents that targets multiple tumor antigens as taught by the prior art, one of skilled in the art could have constructed the therapeutic composition of Granda to include EGFR as second tumor associated antigen.
Response to 103 Arguments
Applicant argues that Stuhler does not disclose a therapeutic composition comprising a multispecific antibody and a second binding molecule that competes with that antibody for a binding to a tumor antigen. Applicant argues that Stuhler is directed to a fundamentally different system in which two separate polypeptides must simultaneously bind different target antigens on the same cell before immune- cell-engaging function is restored through complementation. Applicant argues that Stuhler's competitive blocking experiments, relied upon by the Office, do not disclose or suggest a therapeutic composition comprising a competing binding molecule. Applicant argues that the Office further fails to articulate a sufficient rationale why a person of ordinary skill in the art would have modified Granda's multispecific therapeutic construct to include the claimed competing binding molecule. Applicant argues that Stuhler teaches away from the claimed invention. Applicant argues that that the Office has not identified any disclosure in Granda, Stuhler or Finnefrock suggesting that a competing binding molecule should be used for this purpose. Applicant argues that Finnefrock does not remedy the deficiencies of Granda and Stuhler. Applicant argues that the rejection is the result of impermissible hindsight reconstruction.
Applicants’ arguments have been considered but are not persuasive. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. It is the combination of all of the cited and relied upon references which made up the state of the art with regard to the claimed invention. Applicant's claimed invention fails to patentably distinguish over the state of the art represented by the cited references taken in combination. 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).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In the instant case, Applicants have argued the secondary references individually and failed to consider the combined teaching with Granda to render the invention obvious.
Examiner provides summary of references below:
The primary reference, Granda, teaches that multispecific binding molecules engage at least two tumor associated antigens, in addition to a TCR complex, such as CD3, and Granda second binding molecule; such as an immune cell antibody, which may be administered simultaneously or consecutively. Granda also teaches that the multivalent antibody comprises an Fc region, and wherein the third variable domain and the second variable domain are associated with an Fc region, and the first variable domain is linked to the third variable domain.
Although Granda does not teach that the multivalent antibody competes with the second binding molecule, the Examiner relied on secondary references to render this obvious:
The secondary reference, Stuhler, teaches a set of polypeptides that comprise the following: (1) a first polypeptide that binds to antigen "A1", (2) a second polypeptide binds to target "A2", and (3) a functional domain. Stuhler further teaches that these antigens "A1" and "A2" are different from one another, that the targeting moiety that targets the antigen are variable domains. Stuhler teaches that it would be advantageous to target cells that simultaneously express a combination of antigens. Stuhler exemplifies that these polypeptides in competitive blocking experiments as shown in Figures 6 and 7. In Figure 7, Stuhler teaches that the results of these competitive binding clearly indicates that two respective “tridomain constructs” have to bind simultaneously onto the surface of a cell in order to restore or to complement T cell engaging function”. [0447] Stuhler was used in this rejection to demonstrate known competitive binding methods when two antibodies are administered. Granda already teaches the multivalent antibody.
The purpose of Finnefrock was to demonstrate known uses of binding molecules that bind to PD-L1.
Thus, given the known methods of constructing a multivalent antibody comprising first and second variable domains that bind to tumor antigens, and a third variable domain that binds to an immune cell engaging agent, given the known methods of combining this antibody with a second antibody or binding molecule as taught by Granda, and given the known methods of other binding molecules that target tumor antigens and known mechanisms of competitive binding to the same antigen, one of skilled in the art could have pursued adding the second binding molecule that targets a tumor associated antigen to the multivalent antibody of Granda, with a reasonable expectation of success.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH A ALSOMAIRY whose telephone number is (571)272-0027. The examiner can normally be reached Monday-Friday 7:30 AM to 5:30 PM.
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/SARAH A ALSOMAIRY/Examiner, Art Unit 1646
/Zachariah Lucas/Supervisory Patent Examiner, Art Unit 1600
