DETAILED ACTION
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 .
Claim Status
Claims 9-11, 14-15, 18, 25, 27-28, 30-31, 33, 35-36, 39, and 41-50 are cancelled. Claims 1-8, 12-13, 16-17, 19-24, 26, 29, 32, 34, 37-38, and 40 are pending and currently under consideration for patentability under 37 CFR 1.104.
Priority
This application is a 371 of PCT/US2022/077041 (filed on 09/26/2022) which claims benefit of Provisional U.S. Application No. 63/248,322 (filed on 09/24/2021). Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Claims 1-8, 12-13, 16-17, 19-24, 26, 29, 32, 34, 37-38, and 40 have an effective filing date of 09/24/2021 corresponding to Provisional U.S. Application No. 63/248,322.
Information Disclosure Statement
The information disclosure statement(s) filed on 03/21/2024 and 07/30/2026 has/have been considered. Signed copies are enclosed.
Claim Objections
Claims 1-4, 6-8, 12, 16-17, 19-24, 26, 29, 32, 34, 37-38, and 40 are objected to because of the following informalities:
Claims 1-3, 16-17, 19-24, 26, and 29: the claims should be renumbered so that the claims depend on claims previously set forth (see 112(d) rejection of claim 1 for more information).
Claims 1 and 37: the extra space after “The” in line 1 should be deleted”.
Claims 2-4: “drive” should be replaced with “drives”.
Claims 6-7, 12, 16-17, 21, 26, 29, 38, and 40: the extra space after “recombinant antigen binding molecule of” should be deleted.
Claims 6-7 and 12: a space after claim should be added.
Claim 7: “VHH based” should be replaced with “VHH-based”.
Claim 8: the extra space before “immune checkpoint protein” should be deleted.
Claim 17: “CH3 domain” should be replaced with “CH3 domains”.
Claim 24: the extra space before “IL7” should be deleted.
Claim 32: “CD 28” should be replaced with “CD28”.
Claim 34: the extra space before “DAP12” should be deleted.
Claim 38: “subunit” should be replaced with “subunits”.
Appropriate correction is required.
Claims 2-3 are objected to under 37 CFR 1.75 as being a substantial duplicate of claim 1 (see 112(b) and 112(d) rejections for more information). When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - 35 USC § 112(a)
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 21-24 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.
Instant claim 21 is drawn to an antibody-derived recombinant antigen binding molecule comprising antigen binding domains “wherein at least one antigen binding domain is specific for binding to a tumor associated antigen, a tumor specific antigen, a leukocyte antigen, an effector cell receptor, a cytokine receptor, a Toll-like receptor (TLR), a phagocytic receptor, or an immune checkpoint protein” (lines 2-5). Instant claims 22-24 further specify various tumor associated antigens (instant claim 22), effector cell receptors (instant claim 23), cytokine receptors (instant claim 24), or immune checkpoint proteins (instant claim 24).
The instant specification states “’antigen binding domain’ is any structural motif that is capable of associating with and binding to an antigen” (¶ 0047). The term for antigen binding domain as defined by the instant specification is incredibly broad and does not specify the minimum number of CDRs for binding i.e. they can contain less than 6 CDRs. Furthermore, the instant specification states a variety of antigens can be targeted within these antigen classes. For example, (i) tumor associate antigens include Trop2, Her2, B7H3, FAPa, CD19, CD22, MR1, CD1d, MICA/B, ULBP, Claudin18.2, MARCO, GPC3, Galectin-9, and NKp44L; (ii) effector cell receptors include TCRs, NK receptors, CD137, OX40, CD40, ICOS, CD2, CD28, phagocytic receptors, and TLRs; (iii) cytokine receptors include IL15, IL12, and IL7; and (iv) immune checkpoint proteins include PD-1, PD-L1, Lag3, B7H3, TIGIT, TIM3, TREM2, Siglec15, phosphatidylserine (PS), and CTLA-4 (¶ 0079). Therefore, this functional claim language encompasses a broad genus of structurally distinct antibody-derived recombinant antigen binding molecules targeting various antigens which may contain less than 6 CDRs.
Antigen binding domains include but are not limited to Fabs, scFvs, VHHs, full-length antibodies, and antibody-drug conjugates, which have distinct structures and functions. For example, Sifniotis et al. (Current Advancements in Addressing Key Challenges of Therapeutic Antibody Design, Manufacture, and Formulation, Antibodies, 2019) state there are numerous formats to address challenges in antibody therapeutics (Pg. 14, ¶ 4, lines 4-5). For example, antibody fragments show “better tissue penetration and biodistribution than whole mAb therapeutics; however, a pitfall of smaller peptides lacking an Fc region is a highly reduced in vivo half-life and poor retention times” (Sifniotis et al., Pg. 11, last ¶, lines 1-3). Therefore, antigen binding domains encompass a variety of species, each with their own advantages and disadvantages.
Sevy and Meiler (Antibodies: computer-aided prediction of structure and design of function, Microbiol Spectrum, 2014) state “antibodies pose formidable challenges for protein structure prediction and design due to their large size and highly flexible loops in the complementarity-determining regions” (Pg. 1, Abstract, lines 6-9). Consequently, an antibody’s structure cannot be predicted from function alone accurately i.e. stating the antigen binding domains binds a tumor associated antigen, tumor specific antigen, leukocyte antigen, effector cell receptor, cytokine receptor, TLR, phagocytic receptor, or immune checkpoint protein is not a sufficient description.
The antibody-derived recombinant antigen binding domain can comprise more than one antigen binding domain targeting the recited classes in instant claims 21-24 i.e. it is multispecific. Dickopf et al. Format and geometries matter: Structure-based design defines the functionality of bispecific antibodies, Comput Struct Biotechnol J, 2020) state “[t]here is no ‘standard procedure’ to achieve [the generation of bispecific antibodies with desired functionalities], it rather has to be tackled on a case-by-case basis depending on the under lying biology and structural conditions” (Pg. 1226, ¶ 6, lines 3-5). As “the design and choice of format can have a profound impact on the antibody functionality” (Dickopf et al., Pg. 1221, Abstract, lines 2-3), particularly in regard to multispecific formats, it is not possible to predict the structures encompassed in a genus of multispecific antibody-derived recombinant antigen binding molecules.
Furthermore, the instant specification does not specify how to create antigen binding domains that exhibit the desired biological activity (i.e. retain the ability to bind the various antigens recited in instant claims 21-24) nor the minimal number of CDRs required (i.e. the antibody fragment can contain less than 6 CDRs). Wong et al. (Comparative Analysis of the CDR Loops of Antigen Receptors, Front Immunol, 2019) teach “[a]ll six antibody CDRs can be involved in antigen recognition... As the CDRs form the majority of the binding site, their conformations are critical to the binding” (Pg. 2, column 1, ¶ 1, lines 9-15). This teaching indicates all six CDRs can be required for antigen binding.
As such, instant claims 21-24 are drawn to a genus of antibody-derived recombinant antigen binding molecules. The instant application broadly identifies numerous antigen classes for the antigen binding domain to bind (i.e. tumor associated antigens, tumor specific antigens, leukocyte antigens, effector cell receptors, cytokine receptors, TLR, phagocytic receptors, and immune checkpoint proteins). However, the instant specification provides support for only a limited number of antigen binding domains comprising the antibody-derived recombinant antigen binding molecule. Table 1 (¶ 0076) and Tabel 2 (¶ 0091) provide antigen binding domains for Trop2, CD137, MR1, DR5, MICA, MICB, ULBP, IL-15, IL-15Rα, PD-L1, and PD-1.
However, Applicant is claiming a large and structurally diverse genus of antibody-derived recombinant antigen binding molecules. Absent empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically (i) the structures of antibody-derived recombinant antigen binding molecules and (ii) which antigens they bind. Applicant uses the functional language of binding a tumor associated antigen, tumor specific antigen, leukocyte antigen, effector cell receptor, cytokine receptor, TLR, phagocytic receptor, or immune checkpoint protein as recited in instant claims 21-24 to define the genus which is not sufficient as it is difficult to predict structure from function, particularly in multispecific formats (see Sevy and Meiler and Dickopf et al.), and it is generally known in the art that 6 parental CDRs are needed for binding (see Wong et al.).
Accordingly, Applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed genus and Applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application, including “the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention” (MPEP 2163[II][A][2]).
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. As previously indicated, Applicant has disclosed a limited number of species within the genus claimed. However, given the large number of species encompassed by the genus claimed as well as the high level of structure variation that would be displayed by members of the claimed genus, the disclosure of a subset of adequately described species is not sufficiently representative of the entire genus.
Absent a description of the at least minimal structural features correlating with a functional ability to bind a tumor associated antigen, tumor specific antigen, leukocyte antigen, effector cell receptor, cytokine receptor, TLR, phagocytic receptor, or immune checkpoint protein as recited in instant claims 21-24 which are shared by members of a genus of antibody-derived recombinant antigen binding molecule, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish the structures of the antigen binding domains that confer the ability to bind the recited antigen classes.
Although screening techniques can be used to find antibody-derived recombinant antigen binding molecules that bind the recited antigens of instant claims 21-24, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the ‘written description’ requirement is broader than to merely explain how to ‘make and use’; the applicant must also 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.”
Accordingly, given the difficulty associated with predicting structures of the genus of antibody-derived recombinant antigen binding molecules and given the lack of particularity with which the genus is described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish at least most of the members of the genus to which the claims are directed, and therefore the instant disclosure fails to demonstrate that Applicant was in possession of the claimed invention at the time the application was filed.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention.” Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention" Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
The specification does not reasonably convey possession of the subject matter of instant claims 21-24 and thus fails to comply with the written description requirement of 35 U.S.C. 112(a) as a person having ordinary skill in the art cannot reasonably conclude that the applicant had possession of the claimed invention at the time the instant application was filed.
Claim Rejections - 35 USC § 112(b)
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.
Claim 1-8, 12-13, 16-17, 19-24, 26, 29, 32, 34, 37-38, and 40 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.
Regarding claim 1, the relationship between the scaffolds of claims 1 and 4 renders the claim indefinite. Claim 4 requires a scaffold comprising two subunits while claim 1, which is dependent on claim 4, requires a scaffold comprising four subunits. This discrepancy leads to ambiguity regarding the structure of the scaffold. Therefore, it is unclear whether Applicant intended for the scaffold of claim 1 to be (i) further defining the scaffold of claim 4, (ii) replacing the scaffold of claim 4 entirely, or (iii) introducing a second, additional scaffold. Claims 2-3, 16-17, 19-24, 26, and 29 are included in this rejection as they incorporate and/or depend on claim 1.
For the purposes of claim interpretation, the scaffold of claim 1 will be interpreted as replacing the scaffold of claim 4 entirely.
The term “high-affinity binding” in claims 1-4 is a relative term which renders the claim indefinite. The term “high-affinity binding” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The use of “high-affinity binding” renders the affinity (i) between the CL light chain constant region in the first subunit and the CHI heavy chain constant region in the second subunit and (ii) between the CL light chain constant region in the third subunit and the CHI heavy chain constant region in the fourth subunit indefinite. Claims 5-8, 12-13, 16-17, 19-24, 26, 29, 32, 34, 37-38, and 40 are included in this rejection as they incorporate and/or depend on claims 1 and/or 4.
For the purposes of claim interpretation, binding to any degree will read on “high-affinity binding”.
Regarding claim 2, the relationship between the scaffolds of claims 1 and 2 renders the claim indefinite. Claim 1 requires a scaffold comprising four subunits while claim 2, which is dependent on claim 1, requires a scaffold comprising three subunits. This discrepancy leads to ambiguity regarding the structure of the scaffold. Therefore, it is unclear whether Applicant intended for the scaffold of claim 2 to be (i) further defining the scaffold of claim 1, (ii) replacing the scaffold of claim 1 entirely, or (iii) introducing a second, additional scaffold.
For the purposes of claim interpretation, the scaffold of claim 2 will be interpreted as further defining the scaffold of claim 1. It is noted that, with this claim interpretation, claim 2 is a duplicate of claim 1 (see claim objections).
Regarding claim 3, the relationship between the scaffolds of claims 1 and 3 renders the claim indefinite. Claim 1 requires a scaffold comprising four subunits while claim 3, which is dependent on claim 1, requires a scaffold comprising two subunits. Furthermore, the structural components of the subunits differ among the claims. For example, the second antigen binding domain in the second subunit of claim 1 while it is in the first subunit of claim 3. This discrepancy leads to ambiguity regarding the structure of the scaffold. Therefore, it is unclear whether Applicant intended for the scaffold of claim 3 to be (i) further defining the scaffold of claim 1, (ii) replacing the scaffold of claim 1 entirely, or (iii) introducing a second, additional scaffold.
For the purposes of claim interpretation, the scaffold of claim 3 will be interpreted as further defining the scaffold of claim 1, incorporating all limitations for the first and second subunits of claim 1. It is noted that, with this claim interpretation, claim 3 is a duplicate of claim 1 (see claim objections).
Regarding claim 7, the phrase “the antigen binding domain" renders the claim indefinite because it is unclear whether the phrase refers to the first or the second antigen binding domain of claim 4. Claims 8 is included in this rejection as it incorporates and/or depends on claim 7.
For the purposes of claim interpretation, the phrase “the antigen binding domain" will be treated as “the first or the second antigen binding domain”.
Regarding claims 16-17, the phrase “the Fc domain" renders the claim indefinite because it is unclear whether the phrase refers to the Fc domain of the second or the third subunit of claim 1. Claims 19-20 are included in this rejection as they incorporate and/or depend on claim 17.
For the purposes of claim interpretation, the phrase “the Fc domain" will be treated as “the Fc domain of the second or the third subunit”.
Claim 20 recites the limitation "an antigen binding molecule" in line 1. There is insufficient antecedent basis for this limitation in the claim.
For the purposes of claim interpretation, claim 20 will be treated as dependent on claim 19.
Regarding claim 24, the phrase “the cytokine receptor is IL15, IL12, IL7, PD-1, PD-L1, TIGIT, or CTLA-4" renders the claim indefinite because, as the listed molecules do not refer to only cytokine receptors, it is unclear if Applicant made an error in listing the receptors or meant to refer to both cytokine receptors and immune checkpoint proteins.
For the purposes of claim interpretation, the phrase “the cytokine receptor is IL15, IL12, IL7, PD-1, PD-L1, TIGIT, or CTLA-4" will be treated as the phrase “the cytokine receptor is IL15, IL12, or IL7 or the immune checkpoint protein is PD-1, PD-L1, TIGIT, or CTLA-4".
Regarding claim 26, the phrase "the heterodimerization is further stabilized by (i) modifying the interaction between the CL light chain constant region and the CH1 heavy chain constant region, (ii) the addition of a disulfide bridge to the Fc domain, (iii) the addition of a knob-into-hole modification" renders the claim indefinite because the claim is missing a conjunction and it is unclear whether the limitations of (i)-(iii) must all be present or only one must be present. Furthermore, it is unclear in part (i) whether this limitation refers to the interaction between the first and the second subunit or the third and the fourth subunit.
For the purposes of claim interpretation, the phrase will be treated as "the heterodimerization is further stabilized by (i) modifying the interaction between the CL light chain constant region of the first or the third subunit and the CH1 heavy chain constant region of the second or the fourth subunit, (ii) the addition of a disulfide bridge to the Fc domain, and/or (iii) the addition of a knob-into-hole modification".
Regarding claim 29, the phrase “the immunoglobulin hinge region" renders the claim indefinite because it is unclear whether the phrase refers to the immunoglobulin hinge region of the second or the third subunit of claim 1.
For the purposes of claim interpretation, the phrase “the immunoglobulin hinge region" will be treated as “the immunoglobulin hinge region of the second or the third subunit”.
Regarding claim 37, the relationship between the scaffolds of claims 4 and 37 renders the claim indefinite. The structural components of the subunits differ among the claims. For example, the second antigen binding domain in the second subunit of claim 4 while it is in the first subunit of claim 37. This discrepancy leads to ambiguity regarding the structure of the scaffold. Therefore, it is unclear whether Applicant intended for the scaffold of claim 37 to be (i) further defining the scaffold of claim 4, (ii) replacing the scaffold of claim 4 entirely, or (iii) introducing a second, additional scaffold. Claims 38 and 40 are included in this rejection as they incorporate and/or depend on claim 37.
For the purposes of claim interpretation, the scaffold of claim 37 will be interpreted as replacing the scaffold of claim 4 entirely.
Regarding claim 40, the phrase “an antigen binding domain" renders the claim indefinite because it is unclear whether the phrase refers to one of the antigen binding domains of claim 37 or introduces a new antigen binding domain.
For the purposes of claim interpretation, the phrase “an antigen binding domain" will be treated as “the first or the second antigen binding domain”.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 1-3, 16-17, 19-24, 26, 29, 37-38, and 40 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 1 fails to reference to a claim previously set forth, as it is dependent on claim 4 (see MPEP 608.01(n)). Furthermore, claim 1 fails to further limit the subject matter of the claim upon which it depends, claim 4 (see 112(b) rejection for claim interpretation). Claim 4 requires a scaffold comprising two subunits while claim 1 requires a scaffold comprising four subunits. This recitation broadens the scope of claim 1, rather than further limiting the scope. Claims 2-3, 16-17, 19-24, 26, and 29 are included in this rejection as they incorporate and/or depend on claim 1.
For the purposes of claim interpretation, the scaffold of claim 1 will be interpreted as replacing the scaffold of claim 4 entirely.
Claim 2 fails to further limit the subject matter of the claim upon which it depends, claim 1 (see 112(b) rejection for claim interpretation as claim 2 is a duplicate of claim 1).
For the purposes of claim interpretation, any prior art that teaches all limitations of claim 1 will also read on claim 2.
Claim 3 fails to further limit the subject matter of the claim upon which it depends, claim 1 (see 112(b) rejection for claim interpretation as claim 3 is a duplicate of claim 1).
For the purposes of claim interpretation, any prior art that teaches all limitations of claim 1 will also read on claim 3.
Claim 37 fails to further limit the subject matter of the claim upon which it depends, claim 4 (see 112(b) rejection for claim interpretation). The structural components of the subunits differ among the claims. For example, the second antigen binding domain in the second subunit of claim 4 while it is in the first subunit of claim 37. This recitation broadens the scope of claim 37, rather than further limiting the scope. Claims 38 and 40 are included in this rejection as they incorporate and/or depend on claim 37.
For the purposes of claim interpretation, the scaffold of claim 37 will be interpreted as replacing the scaffold of claim 4 entirely.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claims 4, 6, 32, 34 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US20200093861A1 (published 2020-03-26, hereinafter referred to as US ‘861).
Regarding instant claims 4, US ‘861 teaches adoptive T cell therapy using “chimeric antigen receptors” (¶ 0004), also referred to as an antigen binding receptor (¶ 0130, states it is a synonym). US ‘861 further teaches an exemplary antigen binding receptor, as shown in Fig. 1A (see annotation of Fig. 1A below), “wherein the antigen binding moiety is a Fab” (¶ 0138) and the Fab is “fused by a spacer sequence [hinge linker in Fig. 1A] to an anchoring transmembrane domain [ATM in Fig. 1A] which is itself fused to the intracellular signaling domains [CSD in Fig. 1A]” (¶ 0130). US ‘861 further teaches the Fab comprises “a heavy chain composed of the heavy chain variable and constant regions (VH-CH1), and a light chain composed of the light chain variable and constant regions (VL-CL)” (¶ 0141). US ‘861 further teaches “the CH domain or the CL domain [of the Fab] is connected at the C-terminus to the N-terminus of the anchoring transmembrane domain” (¶ 0023), indicating the CH and CL contain the C-termini while the VH and VL contain the N-termini.
[AltContent: arrow][AltContent: textbox (First antigen binding domain of the first subunit (contains N-terminus))][AltContent: arrow][AltContent: textbox (CH1 of the first subunit (contains C-terminus))][AltContent: arrow][AltContent: arrow][AltContent: textbox (Second antigen binding domain of the second subunit (contains N-terminus))][AltContent: textbox (CL of the second subunit (contains C-terminus))][AltContent: arrow][AltContent: textbox (Hinge region)][AltContent: arrow][AltContent: arrow][AltContent: textbox (Transmembrane domain)][AltContent: textbox (Intracellular signaling domain)]
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US ‘861 further teaches the VH and VL contain CDRs “involved in antigen recognition” (¶ 0150), indicating the VH and VL are antigen binding domains. US ‘861 further teaches the CL can be an IgG “κ (kappa) or λ (lambda)” (¶ 0148). US ‘861 further teaches “to improve correct pairing… modifications are introduced in the… CH1 and CL domains” (¶ 0605) to facilitate Fab self-binding, indicating these modifications improve the heterodimerization and binding (i.e. pairing) of the CH1 and CL regions. These teachings collectively read on an antibody-derived recombinant antigen binding molecule (i.e. antigen binding receptor or CAR) comprising a scaffold (i.e. the structure of Fig. 1A) with:
a first subunit, comprising from the N-terminus to the C-terminus, a first antigen binding domain (i.e. VH of the Fab which contains the N-terminus) and a CH1 heavy chain constant region (i.e. CH1 of the Fab which contains the C-terminus);
the second subunit, comprising from the N-terminus to the C-terminus, a second antigen binding domain (i.e. VL of the Fab which contains the N-terminus) and a CL light chain constant region of an IgK or an IgX (i.e. CL of the Fab which contains the C-terminus);
the first subunit and the second subunit are linked to a chimeric antigen receptor, wherein the chimeric antigen receptor comprises a hinge region (i.e. linker), a transmembrane domain (i.e. anchoring transmembrane domain [ATM]), and a intracellular signaling domain (i.e. co-stimulatory domain [CSD]); and
the high-affinity binding (i.e. pairing) between the CH1 heavy chain constant region in the first subunit and the CL light chain constant region in the first subunit drive heterodimerization of the molecule (i.e. Fab self-binding).
Regarding instant claim 6, US ‘861 further teaches the heavy chain is from IgG2 (¶ 0139), reading on CH1 from the heavy chain is also from IgG2.
Regarding instant claims 32 and 34, US ‘861 further teaches the exemplary antigen binding receptor of Fig. 1A “comprises the CD28 transmembrane domain (instant claim 32)… and a fragment of CD3z as stimulatory signaling domain (instant claim 34)” (¶ 0617; ¶ 0300, indicates stimulatory signaling domain of CD3z is an intracellular domain of CD3z; ¶ 0282, indicated CD28 is from a T cell). These teachings read on the transmembrane domain is from a CD28 T cell (instant claim 32) and the intracellular signaling domain is CD3z (instant claim 34).
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 1-3, 16-17, 19, 21-23, 26, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over US20200093861A1 (published 2020-03-26, hereinafter referred to as US ‘861) in view of US20150119555A1 (published 2015-04-30, hereinafter referred to as US ‘555).
US ‘861 is as discussed above and incorporated by reference herein. US ‘861 teaches an antigen binding receptor (also referred to as a chimeric antigen receptor) including (i) end termini locations of VH/CH1/VL/CL, (ii) modifications to stabilized heterodimerization of CH1 and CL pairings, (iii) CH1 is from IgG, and (iv) CL is from Ig kappa as fully described in the 102 rejection section.
US ‘861 does not teach additional scaffold architecture (instant claims 1-3), the Fc domain and its modifications (instant claims 16-17, 19, and 26), the specific antigen targeted (instant claims 21-23), nor the length of the immunoglobulin hinge region (instant claim 29). These deficiencies are remedied by US ‘555.
Regarding instant claim 1, US ‘555 teaches “a tetravalent molecule” in Fig. 1K (see annotated Fig. 1K below) containing 4 subunits.
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[AltContent: arrow][AltContent: textbox (First antigen binding domain of the first subunit (contains N-terminus))][AltContent: textbox (CL of the first subunit (contains C-terminus))][AltContent: arrow][AltContent: arrow][AltContent: textbox (Second antigen binding domain of the second subunit (contains N-terminus))][AltContent: arrow][AltContent: textbox (CH1 of the second subunit (contains C-terminus))][AltContent: textbox (Sixth antigen binding domain of the fourth subunit (contains N-terminus))][AltContent: textbox (CH1 of the fourth subunit (contains C-terminus))][AltContent: textbox (CL of the third subunit (contains C-terminus))][AltContent: textbox (Fourth antigen binding domain of the third subunit (contains N-terminus))][AltContent: arrow][AltContent: arrow][AltContent: arrow][AltContent: arrow][AltContent: textbox (Immunoglobulin hinge region)][AltContent: arrow][AltContent: textbox (Third antigen binding domain of second subunit)][AltContent: arrow][AltContent: arrow][AltContent: textbox (Fifth antigen binding domain of third subunit)][AltContent: arrow][AltContent: textbox (CH2s and CH3s of Fc region of second and third subunits)]
Please refer to the 102 rejection for how the end termini are known in the art as taught by US ‘861. This teaching reads on the antibody-derived recombinant antigen binding molecule (i.e. tetravalent molecule) comprising a scaffold (i.e. the structure of Fig. 1K) with:
the first subunit, comprising from the N-terminus to the C-terminus, a first antigen binding domain (i.e. VL) and a CL light chain constant region;
the second subunit, comprising from the N-terminus to the C-terminus, a second antigen binding domain (i.e. VH), a CH1 heavy chain constant region, an immunoglobulin hinge region, a heavy chain Fc domain from an IgG (i.e. CH2 and CH3), and a third antigen binding domain (i.e. VL and VL);
the third subunit, comprising from the N-terminus to the C-terminus, a fourth antigen binding domain (i.e. VL), a CL light chain constant region, an immunoglobulin hinge region, a heavy chain Fc domain (i.e. CH2 and CH3), and a fifth antigen binding domain (i.e. VL and VL); and
the fourth subunit, comprising from the N-terminus to the C-terminus, a sixth antigen binding domain (i.e. VH) and a CH1 heavy chain constant region.
Regarding instant claims 2-3, as they are duplicates of instant claim 1 (see 112(b) rejections), prior art that teaches all limitations of instant claim 1 also reads on instant claims 2-3.
Regarding instant claim 16 and 26, US ‘555 further teaches “inter-chain disulfide bonds (instant claim 16)…. that prevent dimerization with homotypic CH3 domains (instant claim 26)” (¶ 0013) in the Fc domain, indicating heterodimerization is favored when homodimerization is actively impeded. This teaching reads on the Fc domain comprises a disulfide bridge (instant claim 16) that stabilizes heterodimerization (instant claim 26).
Regarding instant claim 17, US ‘555 further teaches the Fc domain is from an IgG1 (¶ 0069), reading on the Fc domain comprises a CH2 and CH3 (see Fig. 1K) from an IgG.
Regarding instant claim 19, US ‘555 further teaches the “C-terminal region” (¶ 0089) of CH3 is modified with a scFv (see Fig. 1K), reading on the C-termini of the two CH3 domains are linked to an antigen binding molecule (i.e. scFv) as depicted in Fig. 1K.
Regarding instant claims 21-22, US ‘555 further teaches the antibody binds “a tumor associated antigen” (¶ 0076) (instant claim 21), specifically Her2 (¶ 0078) (instant claim 22). This teaching reads on an antigen binding domain binding a tumor associated antigen (instant claim 21), specifically Her2 (instant claim 22).
Regarding instant claim 23, US ‘555 further teaches the antibody binds the effector cell receptor TCR (¶ 0105).
Regarding instant claim 29, US ‘555 further teaches “the [immunoglobulin] hinge region is defined by amino acids 217 to 231” i.e. it is 5 amino acids in length. This teaching reads on the immunoglobulin hinge region is 5 amino acids in length, falling within the range of 3-9 amino acids.
US ‘555 further teaches multispecific molecules of their invention can “recognize both an antigen on target cells… and the antigen specific T cell receptor” (¶ 0004), giving motivation for using a multispecific molecule as it can direct immune cells to target cells for therapeutic purposes.
Multivalent molecules were known and used prior to the effective filing date of the application. In addition, US ‘861 and US ‘555 are in analogous arts (i.e. antigen binding molecules). US ‘555 teaches multispecific molecules can recognize both target cells and T cells simultaneously, while US ‘861 teaches monospecific molecules that can recognize one antigen at a time i.e. either a target cell or a T cell but not both simultaneously. Therefore, a person having ordinary skill in the art wishing to engage both target cells and T cells simultaneously could do so using the multispecific molecule of US ‘555, a quality that the monospecific molecule of US ‘861 lacks. Engaging both a target cell and T cell simultaneously via the multispecific molecule of US ‘555 would direct the T cells to the target cells for destruction, important for therapeutic treatments. Thus, there is motivation for using the multispecific format as taught by US ‘555 in the antigen binding receptor as taught by US ‘861 to direct immune cells to target cells for therapeutic purposes like cancer treatment.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome 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.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. US ‘555 teaches multispecific molecules can recognize both target cells and T cells simultaneously) would have led one of ordinary skill to modify the prior art reference (i.e. the antigen binding receptor as taught by US ‘861) to arrive at the claimed invention. There is a reasonable expectation of success as US ‘555 teaches multispecific formats comprising Fabs, applicable to the Fab containing antigen binding receptor of US ‘861. US ‘555 teaches numerous ways to incorporate Fabs into multispecific formats, indicating the structural rearrangement is modular and predictable.
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to use the multispecific format as taught by US ‘555 in the antigen binding receptor as taught by US ‘861 to direct immune cells to target cells for therapeutic purposes like cancer treatment.
Claims 5 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over US20200093861A1 (published 2020-03-26, hereinafter referred to as US ‘861) in view of US20150119555A1 (published 2015-04-30, hereinafter referred to as US ‘555) as applied to claim 1 above, and further in view of Morrissey et al. (Chimeric antigen receptors that trigger phagocytosis. Elife. 2018 Jun 4;7:e36688).
US ‘861 and US ‘555 are as discussed above and incorporated by reference herein. US ‘861 and US ‘555 teach the antigen binding molecule of instant claim 1 as fully described in the previous 103 rejection section, the 103 being incorporated here.
US ‘861 and US ‘555 do not teach a phagocytic CAR (instant claim 5) with an scFv antigen binding domain (instant claim 7). This deficiency is remedied by Morrissey et al.
Regarding instant claim 5, Morrissey et al. teach “Chimeric Antigen Receptors for Phagocytosis (CAR-Ps)” (Pg. 1, Abstract), reading on a phagocytic CAR.
Regarding instant claim 7, Morrissey et al. further teach a CAR-P wherein the antigen binding domain is an scFv (Pg. 6, Fig. 3b, alpha CD19 scFv depicted in purple).
Morrissey et al. further teach CAR-Ps “direct macrophages to engulf specific targets, including cancer cells… CAR-P expressing murine macrophages reduce cancer cell number in co-culture by over 40%” (Pg. 1, Abstract, line 4 to the end), indicating CAR-Ps are powerful tools for cancer treatment.
CAR-Ps were known and used prior to the effective filing date of the application. In addition, US ‘861 and US ‘555 are in analogous arts (i.e. antigen binding molecules) while US ‘861 and Morrissey et al. are in analogous arts (i.e. CARs). Since Morrissey et al. teach CAR-Ps direct macrophages to engulf cancer cells, there is motivation for using CAR-Ps as taught by Morrissey et al. in the antigen binding molecule as taught by US ‘861 and US ‘555 to eliminate cancer cells in a patient by at least 40% as taught by Morrissey et al.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome 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.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. Morrissey et al. teach CAR-Ps direct macrophages to engulf cancer cells) would have led one of ordinary skill to modify the prior art reference (i.e. the antigen binding molecule as taught by US ‘861 and US ‘555) to arrive at the claimed invention. There is a reasonable expectation of success as Morrissey et al. demonstrate CAR-Ps can comprise antigen binding domains such as scFvs to target specific antigens, applicable to the scFv-containing antigen binding molecules of US ‘861 and US ‘555. The scFv in the CAR-P retains its specificity to its antigen, indicating the combination would be predictably drive phagocytosis.
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to use CAR-Ps as taught by Morrissey et al. in the antigen binding molecule as taught by US ‘861 and US ‘555 to eliminate cancer cells in a patient.
Claims 8, 12-13, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over US20200093861A1 (published 2020-03-26, hereinafter referred to as US ‘861) in view of US20150119555A1 (published 2015-04-30, hereinafter referred to as US ‘555) and Morrissey et al. (Chimeric antigen receptors that trigger phagocytosis. Elife. 2018 Jun 4;7:e36688) as applied to claims 5 and 7 above, and further in view of US20200291089A1 (published 2020-09-17, hereinafter referred to as US ‘089).
US ‘089 teaches multifunctional molecules that include trimeric ligands for treating cancer (Abstract). Regarding instant claims 8, 13, and 24, US ‘089 further teaches the multifunctional molecule contains “the cytokine molecule (e.g., IL-15) (instant claim 8) and the receptor dimerizing domain (e.g., an IL15Ralpha dimerizing domain) (instant claims 13 and 24)… covalently linked” (¶ 0427). This teaching reads on the multifunctional molecule contains natural protein domains from IL-15 (instant claims 8) and IL15 alpha receptor (instant claims 13 and 24).
Regarding instant claim 12, US ‘089 further teaches monomer molecules (i.e. IL-15) “covalently linked, to the C-terminus of the first dimerization molecule” (i.e. IL15 alpha receptor) include a hinge region (¶ 0129), wherein the hinge region is from an Fc domain of an IgG (¶ 0056) i.e. it is an immunoglobulin hinge region. This teaching reads on the N-terminus of an antigen binding domain (i.e. IL-15) is linked to an antigen binding molecule (i.e. IL15R alpha), wherein an immunoglobulin hinge region (i.e. hinge region from Fc region of IgG) links the N-terminus of the antigen binding domain (i.e. N-terminus of IL-15) to the antigen binding molecule (i.e. C-terminus of IL15R alpha).
US ‘089 further teaches “[c]ytokines are proteinaceous signaling compounds that are mediators of the immune response. They control many different cellular functions including proliferation, differentiation and cell survival/apoptosis” (¶ 0421), indicating a multifunctional molecule containing a cytokine would act an immunomodulator to stimulate immune cells
Incorporating cytokine and cytokine receptor domains into antigen binding molecules was known and used prior to the effective filing date of the application. In addition, US ‘861, US ‘555, and US ‘089 are in analogous arts (i.e. antigen binding molecules) while US ‘861 and Morrissey et al. are in analogous arts (i.e. CARs). Since US ‘089 teaches cytokines are immunomodulators that control cellular functions like proliferation and survival, there is motivation for using the cytokine and cytokine receptor domains as taught by US ‘089 in the antigen binding molecule as taught by US ‘861, US ‘555, and Morrissey et al. to increase immune cell proliferation and cytotoxicity to further target cancer cells and boost efficacy of a cancer immunotherapy.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome 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.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. cytokines are immunomodulators that control cellular functions like proliferation and survival) would have led one of ordinary skill to modify the prior art reference (i.e. the antigen binding molecule as taught by US ‘861, US ‘555, and Morrissey et al.) to arrive at the claimed invention. There is a reasonable expectation of success as US ‘089 explicitly teaches both cytokine and cytokine receptor domains together in one molecule, indicating the combination can be incorporated predictably into a multispecific format without issue.
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to use the cytokine and cytokine receptor domains as taught by US ‘089 in the antigen binding molecule as taught by US ‘861, US ‘555, and Morrissey et al. to increase immune cell proliferation and cytotoxicity to further target cancer cells and boost efficacy of a cancer immunotherapy.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over US20200093861A1 (published 2020-03-26, hereinafter referred to as US ‘861) in view of US20150119555A1 (published 2015-04-30, hereinafter referred to as US ‘555) as applied to claims 1, 17, and 19 above, and further in view of US20130039911A1 (published 2013-02-14, hereinafter referred to as US ‘911).
US ‘861 and US ‘555 are as discussed above and incorporated by reference herein. US ‘861 and US ‘555 teach the antigen binding molecule of instant claim 1, 17, and 19 as fully described in the previous 103 rejection section, the 103 being incorporated here.
US ‘861 and US ‘555 do not teach PD-1 as an antigen binding molecule (instant claim 20). This deficiency is remedied by US ‘911.
US ‘911 teaches fusion proteins comprising “Programmed Death-1 (PD-1) Ectodomain” (¶ 0052), reading on PD-1 as an antigen binding molecule.
US ‘911 further teaches the fusion protein produce “the antitumor immune response to eliminate disseminated cancer cell” (¶ 0104), indicating a clinical relevance for treating cancer, and specifically mentions PD-1 ectodomain as a useful antigen binding moiety (¶0116).
Incorporating PD-1 ectodomains into an antigen binding molecule was known and used prior to the effective filing date of the application. In addition, US ‘861, US ‘555, and US ‘911 are in analogous arts (i.e. antigen binding molecules). Since US ‘911 teaches PD-1-containing antigen binding molecules can trigger an antitumor response, there is motivation for using PD-1 ectodomains as taught by US ‘911 in the antigen binding molecule as taught by US ‘861 and US ‘555 to promote T cells to eliminate cancer cells in a cancer immunotherapy.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome 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.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. US ‘911 teaches PD-1-containing antigen binding molecules can trigger an antitumor response) would have led one of ordinary skill to modify the prior art reference (i.e. the antigen binding molecule as taught by US ‘861 and US ‘555) to arrive at the claimed invention. There is a reasonable expectation of success as US ‘911 indicated PD-1 ectodomains can be incorporated into multispecific formats, applicable to the antigen binding molecules taught by US ‘861 and US ‘555. This teaching indicates the combination can be incorporated predictably into a different multispecific format without issue.
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to use PD-1 ectodomains as taught by US ‘911 in the antigen binding molecule as taught by US ‘861 and US ‘555 to promote T cells to eliminate cancer cells in a cancer immunotherapy.
Claims 37-38 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over US20200093861A1 (published 2020-03-26, hereinafter referred to as US ‘861) in view US20160200833A1 (published 2016-07-14, hereinafter referred to as US ‘833).
US ‘861 is as discussed above and incorporated by reference herein. US ‘861 teaches an antigen binding receptor (also referred to as a chimeric antigen receptor) including (i) end termini locations of VH/CH1/VL/CL, (ii) modifications to stabilized heterodimerization of CH1 and CL pairings, (iii) CH1 is from IgG, and (iv) CL is from Ig kappa as fully described in the 102 rejection section.
US ‘861 does not teach additional scaffold architecture (instant claims 37), a TNFSF ligand (instant claim 38), nor the type of antigen binding domain (instant claim 40). These deficiencies are remedied by US ‘833.
US ‘833 teaches “TNF family ligand trimer-containing antigen binding molecules” (Abstract).
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[AltContent: arrow][AltContent: textbox (First antigen binding domain of the first subunit (contains N-terminus))][AltContent: arrow][AltContent: textbox (CH1 of the first subunit (contains C-terminus))][AltContent: textbox (Fc domain)][AltContent: arrow][AltContent: arrow][AltContent: textbox (Second antigen binding domain of first subunit)]Regarding instant claim 37, US ‘833 further teaches the antigen binding molecule depicted in Fig. 2E (annotated below). US ‘833 further teaches the CH1 and CL domains of the antigen binding molecules of the invention are crossed over or exchanged (¶ 0145), indicating the CL of the second subunit is exchanged for the CH1 adjacent to it i.e. creating VH-CL in the second subunit depicted below in Fig. 2E. US ‘833 further teaches “[f]rom N- to C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or a heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3), also called a heavy chain constant region. Similarly, from N- to C-terminus, each light chain has a variable region (VL), also called a variable light domain or a light chain variable domain, followed by a light chain constant domain (CL)” (¶ 0142). US ‘833 further teaches the heavy chain is from IgG and the light chain is from Ig kappa (¶ 0142). US ‘833 further teaches 4-1BBL as depicted on the end terminus of the antigen binding molecule of Fig. 2E is a part of the TNFSF (¶ 0189). These teachings read on an antibody-derived recombinant antigen binding molecule comprising a scaffold (i.e. the structure of Fig. 2E with its CH1 and CL exchanged in the second subunit) with
the first subunit, comprising from the N-terminus to the C-terminus, a first antigen binding domain (i.e. VH), a CH1 heavy chain constant region, an immunoglobulin hinge region, a heavy chain Fc domain from an IgG, and a second antigen binding domain;
the second subunit, comprising from the N-terminus to the C-terminus, a third antigen binding domain (i.e. VH), a CL light chain constant region of an IgK, an immunoglobulin hinge region, a heavy chain Fc domain from an IgG, and a fourth antigen binding domain (i.e. the TNFSF ligand 1-4BBL); and
the TNFSF ligand is linked to a terminal end of the second subunit.
Regarding instant claim 38, US ‘833 further teaches the antigen binding molecule of Fig. 2E comprises “two ectodomains of a TNF ligand family member” (¶ 0031), reading on two subunits of the TNFSF ligand.
Regarding instant claim 40, US ‘833 further teaches the antigen binding molecule of Fig. 2E comprises “Fabs” (¶ 0509).
US ‘833 further teaches “CD137 {4-1BB} signaling is known to stimulate IFNγ secretion and proliferation of NK cells” (¶ 0007), giving motivation for targeting 4-1BB via its ligand in a therapeutic method to improve innate immune response.
Molecules that bind a TNFSF ligand were known and used prior to the effective filing date of the application. In addition, US ‘861 and US ‘833 are in analogous arts (i.e. antigen binding molecules). US ‘833 teaches targeting 4-1BB via its ligands can induce the proliferation of NK cells, there is motivation for using the molecule that binds the TNFSF ligand 1-4BBL as taught by US ‘833 in the antigen binding receptor as taught by US ‘861 to direct improve innate immune response for therapeutic purposes like cancer treatment.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome 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.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. US ‘833 teaches targeting 4-1BB via its ligands can induce the proliferation of NK cells) would have led one of ordinary skill to modify the prior art reference (i.e. the antigen binding receptor as taught by US ‘861) to arrive at the claimed invention. There is a reasonable expectation of success as US ‘833 teaches multispecific formats comprising Fabs, applicable to the Fab containing antigen binding receptor of US ‘861. US ‘833 teaches ways to incorporate Fabs into multispecific formats that target TNFSF receptors, indicating the structural rearrangement is modular and predictable.
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to use the molecule that binds the TNFSF ligand 1-4BBL as taught by US ‘833 in the antigen binding receptor as taught by US ‘861 to direct improve innate immune response for therapeutic purposes like cancer treatment. Further, one of ordinary skill in the art would have had a reasonable expectation of success since ‘833 demonstrated that the co-stimulatory TNF ligand trimer is biologically active and stable.
Conclusion
Claims 1-8, 12-13, 16-17, 19-24, 26, 29, 32, 34, 37-38, and 40 are pending. Claims 1-4, 6-8, 12, 16-17, 19-24, 26, 29, 32, 34, 37-38, and 40 are objected to. Claims 1-8, 12-13, 16-17, 19-24, 26, 29, 32, 34, 37-38, and 40 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jessica M Priest whose telephone number is (571)272-8469. The examiner can normally be reached Mon-Fri 8am-5pm.
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/J.M.P./Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
