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 .
Applicant’s remarks, filed 12/23/2025, are acknowledged and entered into the record. Applicants amended claims 1, 3-5, 7-9, 11, 13-14, 16-17 and 20, and added new claims 21-24 in the remarks of 12/23/2025.
Priority- Foreign
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(a)-(d) and (f) or under 35 U.S.C. 120, 121, 365(a) or (b), or 386(a) is acknowledged. The present application is a Continuation-in-part of application 17/127,283 (US Patent 11524034; issued 12/13/2022), and is drawn from PCT/CN2019/077923, filed 3/13/2019; and claims benefit under 35 U.S.C. (119(a)-(d) to foreign application CN201810636414.1, filed 6/20/2018.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. 17/127,283, filed on 1/11/2022.
Present claims 21 and 23 are directed to a chimeric antigen receptor (CAR) comprising X, wherein X is a tumor-targeting antibody, and wherein X is an anti-CLDN18.2 antibody or antigen-binding domain thereof, such as the anti-CLDN18.2 scFv of instant SEQ ID NO: 3 (specifications, pg. 15). However, none of priority documents CN201810636414.1, PCT/CN2019/077923, or US application 17/127,283 (or US Patent 11524034) contemplates an anti-CLDN18.2 antibody generally, or the anti-CLDN18.2 scFv of instant SEQ ID NO: 3. Therefore, as new matter has been claimed, which was not contemplated in the priority documents, applicants do not receive benefit of the prior-filed applications or issued patents for the claims that recite the anti-CLDN18.2 antibody or scFv; however, claims 1-2, 7, 10-13 and 15-20, drawn to the generic tumor targeting antibody, do find support in priority application CN201810636414.1. Thus, the priority date for instant claims 1-20, 22 and 24 is 6/20/2018, and the priority date for instant claims 21 and 23 is the filing date of the instant application, which is 10/19/2022.
Status of Claims
Claims 1-24 are pending and are being examined on the merits.
Claim Objections-Withdrawn
The objections to claims 1, 4, 7-9, 14 and 16 are withdrawn. Applicants amended the claims to address the minor informalities.
Claim Rejections-Withdrawn
Claim Rejections - 35 USC § 112(b)
The rejection of claim 17 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, is withdrawn. Applicants amended claim 17 to remove the subject matter that caused the indefiniteness issues.
Claim Rejections - 35 USC § 112(a)
The rejection of claim 20 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating a tumor, does not reasonably provide enablement for a method of preventing a tumor, is withdrawn. Applicants amended claim 20 to remove the limitation drawn to “preventing”, thus obviating the issues of enablement.
Double Patenting
The rejection of claims 1-2 and 4-20 on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 5 of U.S. Patent No. 11,524,034; issued 12/13/2022, is withdrawn. Applicants filed a terminal disclaimer over US Patent No. 11,524,034, thus obviating the rejection for nonstatutory double patenting. The terminal disclaimer was filed 12/23/2025, and approved 12/28/2025.
The rejection of claims 1-20 on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 5 of U.S. Patent No. 11,524,034; issued 12/13/2022 in view of Wiltzius et al., (from IDS; WO 2017173256, published 5/10/2017), is withdrawn. Applicants filed a terminal disclaimer over US Patent No. 11,524,034, thus obviating the rejection for nonstatutory double patenting. The terminal disclaimer was filed 12/23/2025, and approved 12/28/2025.
Claim Rejections – New, Maintained
Claim Rejections - 35 USC § 112
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.
Claim 18 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.
Claim 18 recites the limitation "comprising " in line 1. There is insufficient antecedent basis for this limitation in the claim. No claims are drawn to, or even recite, a polynucleotide encoding the CAR of claim 1. Thus, there is insufficient antecedent basis for “the polynucleotide” of claim 18.
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.
Claims 1-14 and 16-23 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 specification discloses anti-CD20 scFv constructs whereby the construct comprises a 20BBZ domain of SEQ ID NO: 1, and wherein the intracellular domain of M is IL2Rb (example 1, pg. 34, para. 0134), IL4Ra (example 2, pg. 35, para. 0140), IL7Ra (example 3, pg. 35, para. 0146), IL9Ra (example 4, pg. 36, para. 0152), or IL21Ra (example 5, pg. 37, para. 0158). Further, the specification discloses a single anti-CD19 construct comprising the 19BBZ of SEQ ID NO: 17 and whereby M is IL7Ra (example 9, pg. 39, para. 0170), a single anti-CLDN18.2 construct comprising the CLDN18.2-BBZ of SEQ ID NO: 19 and whereby M is IL21Ra (example 12, pg. 40, para. 0180), a single anti-EGFR construct comprising EGFR-BBZ of SEQ ID NO: 21, and whereby M is IL21Ra (example 15, pg. 42, para. 0190). None of the examples disclose a hinge or transmembrane (TM) domain, but rather use a BBZ fusion construct, which is not described. Further, while various anti-CD20 constructs, comprising a 20BBZ domain, where made whereby M is IL2Rb, IL4Ra, IL7Ra, IL9Ra or IL21Ra, the single anti-CD19 construct, comprising a 19BBZ domain, has an M of IL7Ra, the single anti-CLDN18.2 construct, comprising a CLDNBBZ domain, has an M of IL21Ra, and the single anti-EGFR construct, comprising a EGFRBBZ domain, has an M of IL21Ra. The structures corresponding to the 20BBZ, 19BBZ, CLDNBBZ and EGFRBBZ are not in and of themselves described on the basis of function within the molecule, other than comprising the tumor targeting domain and a single fusion of a 4-1BB/CD3zeta components, which might represent a single embodiment of Y-CD3zeta. The claims are drawn to embodiments whereby Y may be “an intracellular domain of” 4-1BB, or any of ICOS , CD28, CD27, HVEM, LIGHT, CD40L, OX40, DR3, GITR, CD30, TIM1, SLAM, CD2, or CD226; and further, whereby M may be “an intracellular domain of” any of IL2Ra, IL2Rb, IL4Ra, IL7Ra, IL9Ra, IL15Ra or IL21Ra. Thus, the claims are drawn to multiple genuses of the CAR. For example, the claims are drawn to a genus of “any tumor targeting antibody” CARs, comprising a number of unidentified intracellular domains whereby “an intracellular domain of” any of the listed molecules may be structurally distinct. Thus, the claims are drawn to a genus of CARs, whereby X is a genus of structurally distinct species, whereby the Y domain is a genus of structurally distinct species selected from any one of the molecules listed, and M is a genus of structurally distinct species selected from any one of the molecules listed. Therefore, the claims encompass a vast number of structurally distinct embodiments, with no teaching of the functional requirements of any of the claimed structures other than the ability to target a tumor, and whereby the enormous number of different combinations claimed have only a single shared structural feature of comprising a third signaling domain of N, which itself may be any intracellular domain of IL2Rg, and may also be structurally distinct. For example, there are at least 105 different embodiments of Y+M claimed, if any one of the listed intracellular domains relates to a single, specific amino acids sequence structure. Allowing “an intracellular domain of” expands the total number of Y+M combinations exponentially, depending on how many different sequence structures correspond to “an intracellular domain of” for each molecule listed. If the tumor targeting domain (X) was limited to those of claim 3, whereby 10 genuses of antibodies are listed by their target, there are over 1,050 different embodiments of X+Y+M. Further, allowing any variant species of anti-CD20 antibodies, anti-CD19 antibodies, etc., whereby numerous alternative species are known in the art for each genus, exponentially expands the total number of 1,050 different CARs encompassed by the claims. Further, claim 1 is not limited to the 10 anti-tumor targeting antibodies, and may be any anti-tumor targeting antibody in the art; thus exponentially expanding the number of species encompassed by the CAR of claim 1 to an astronomical number of variant species.
The considerations that are made in determining whether a claimed invention is supported by an adequate written description are outlined by the published Guidelines for Examination of Patent Applications Under the 35 U.S.C. 112, para. 1, ``Written Description'' Requirement (Federal Register; Vol. 66, No. 4, January 5, 2001; hereinafter “Guidelines”). Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described. Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997). See also: University of Rochester v. G.D. Searle & Co., 69 USPQ2d 1886 1892 (CA FC 2004).
Thus, an original claim may provide written description for itself, but it must still be an adequate written description, which establishes that the inventor was in possession of the invention. In this instance, the claims are drawn to a “chimeric antigen receptor” (CAR). According to claim 1 the CAR has a structure that is represented by X-Y-CD3zeta-M-N, whereby X is any tumor targeting antibody, Y is an intracellular domain selected from a group of structurally distinct costimulatory receptors, and (M) is an intracellular domain selected from a group of structurally distinct second intracellular signaling domains, and N is any intracellular domain of IL2Rg. It unclear of what particular elements the CAR is comprised because claim 1 does not define the structural content of the domains. Nevertheless, it would appear that the claimed CAR may lack some of the elements that according to the disclosure are essential (e.g., a transmembrane domain adjoining X, which is a tumor-targeting antibody or a ligand or a receptor capable of specifically binding to a tumor, and which is presumably an extracellular domain, and Y, which is an intracellular domain. Even so, it is evident that the claimed CAR comprises an intracellular domain, which is of a co-stimulatory receptor (e.g., ICOS), but it is not clear what structure it must have or what particular function it be capable of performing. Unlike the presumed “extracellular ligand binding domain”, which is described as having the capability of targeting or binding to a tumor, the “intracellular domain” need not have any particular function. While according to claim 1 it is of or derived from a co-stimulatory receptor (e.g., ICOS), it is not clear what portion of the co-stimulatory receptor (e.g., ICOS) is to be regarded as an intracellular domain, which is suitably used to construct claimed invention, particularly since it is not evident which functional properties it must possess. Then, even if it might be presumed that the claimed CAR necessarily further comprises “a transmembrane domain”, which must presumably span the membrane to connect the intracellular domain and the extracellular domain of the CAR, it is thought that it is not any and all “transmembrane domains” that are suitably used to produce the claimed CAR, at least not if it is to be used as intended. Although it is presumed that whatever it is it must span the plasma membrane of a cell it is not evident which polypeptides will or will not be found suitable, especially since it is well known that different transmembrane domains are not reasonably considered equivalents. This is, for example, because while some transmembrane domains traverse the membrane only once, others traverse the membrane multiple times. Here it is noted that no one element of the conventional CAR, typically comprising an extracellular ligand binding domain, a spacer, a transmembrane domain, and an intracellular (cytoplasmic) signaling domain, has been found to be purely structural. Even the transmembrane domain, which might at once been regarded to have played only a structural role, has been found to impart particular functional properties upon the CAR. Bridgeman et al. (J. Immunol. 2010 Jun 15; 184 (12): 6938-49) found, for example, that CARs containing the CD3zeta transmembrane domain can form a complex with the endogenous TCR that may be beneficial for optimal T cell activation, a property that could be abolished by altering the structure of the transmembrane domain by amino acid substitution (see entire document; e.g., the abstract). It is therefore reasonable to question whether a CAR such as that to which claim 1 is directed, which might comprise any given “transmembrane domain” or which need not comprise a spacer or stalk region such as an immunoglobulin hinge domain, will function as it should. This position is further supported by the teachings of Hudecek et al. (Clin. Cancer Res. 2013 Jun 15; 19 (12): 3153-64), which describes a study in which different CARs comprising spacers of varying length derived from the extracellular lgG4-Fc spacer domain were compared (see entire document) and in which it was found that CARs with short “hinge-only spacers" were substantially more functional than CARs with relatively longer "hinge-CH2-CH3 spacers” (see entire document; e.g., the abstract). Such results suggest that no one element of a conventional CAR can be taken for granted or presumed to function as necessary regardless of its structure; and accordingly since the claims are drawn to a plurality of structurally disparate CARs comprising, for example, any given “transmembrane domain”, but not necessarily a hinge, it is submitted that the description of the exemplary CARs by this application should not be regarded as sufficient to adequately describe with the requisite clarity and particularity at least a substantial number of members of the claimed genus of structurally disparate CARs. Applicant is reminded that “generalized language may not suffice if it does not convey the detailed identity of an invention.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1892 (CAFC 2004). “Patents are not awarded for academic theories, no matter how ground-breaking or necessary to the later patentable inventions of others. ‘[A] patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.’ Id. at 930 n. 10 (quoting Brenner, 383 U.S. at 536, 86 S.Ct. 1033). Requiring a written description of the invention limits patent protection to those who actually perform the difficult work of ‘invention’ — that is, conceive of the complete and final invention with all its claimed limitations — and disclose the fruits of that effort to the public.” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353, 94 U.S.P.Q.2d 1161, 1173-1174 (Fed. Cir. 2010). “As this court has repeatedly stated, the purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.’ Rochester, 358 F.3d at 920 (quoting Reiffin v. Microsoft Corp., 214 F.3d 1342, 1345 (Fed. Cir. 2000)). It is part of the quid pro quo of the patent grant and ensures that the public receives a meaningful disclosure in exchange for being excluded from practicing an invention for a period of time. Enzo, 323 F.3d at 970.” Id. 598 F.3d at 1353-1354. With regard to the presumed extracellular domain of the claimed CAR, which is either a ligand (a molecule that binds to a receptor) or a receptor (a molecule that binds to a ligand), which is capable of binding to a tumor, the specification appears to adequately describe an antibody (e.g., an scFv) that binds to a tumor antigen but it does not adequately describe with the requisite clarity and particularity at least a substantial number of the ligands and/or receptors that are used to construct the claimed invention. These molecules are only described by their function alone (i.e., the ability to bind to a tumor) but it is not possible to adequately describe an invention or a part thereof by describing the function alone that must be achieved thereby. Here Applicant is duly reminded that the Federal Circuit has decided that a generic statement that defines a genus of substances by only their functional activity, e.g., the ability to bind to a tumor, does not provide an adequate written description of the genus. See The Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The Court indicated that while applicants are not required to disclose every species encompassed by a genus, the description of a genus is achieved by the recitation of a precise definition of a representative number of members of the genus, such as by reciting the structure, formula, chemical name, or physical properties of those members, rather than by merely reciting a wish for, or even a plan for obtaining a genus of molecules having a particular functional property. The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of genus must be capable of doing, not of the substance and structure of the members. Although Lilly related to claims drawn to genetic material, the statute applies to all types of inventions. “Regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods”. University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1894 (CAFC 2004). The claimed method depends upon finding a molecule that has the ability to bind to a tumor, which is suitably used to construct the claimed invention; without such a molecule, it is impossible to practice the invention. In this case, since the claims are so broad, and the disclosure is so comparably limited, it is submitted that any alleged conception has no more specificity than simply a wish to know the identity of any material with that requisite biological properties, which can be used to practice the claimed method, so as to achieve the claimed objectives. In such instances, the alleged conception fails not merely because the field is unpredictable or because of the general uncertainty surrounding experimental sciences, but because the conception is incomplete due to factual uncertainty that undermines the specificity of the inventor’s idea of the invention. Burroughs Wellcome Co. v. Barr Laboratories Inc., 40 F.3d 1223, 1229, 32 USPQ2d 1915, 1920 (Fed. Cir. 1994). Reduction to practice in effect provides the only evidence to corroborate conception (and therefore possession) of the invention.
Lastly, since the claims are not necessarily limited to known materials having the properties of the claimed “chimeric antigen receptor” and/or a cell comprising the claimed “chimeric antigen receptor”, which is administrated so as to prevent or treat a tumor, but rather to such material that might be identified, given the bid set forth in the instant disclosure to do so, it is noted that one cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481, 1483 (Bd. Pat. App. & Int. 1993). Thus, it is submitted that the disclosure describing the claimed subject matter fails to satisfy the written description requirement set forth under 35 U.S.C. § 112, first paragraph. Claim 1 is rejected for lacking adequate descriptive support across the enormous breadth of the claimed genuses of CARs, whereby the structural specificity of each of the necessary TM-Y-CD3zeta-M-N domains is not specified, and for which every claimed species comprises a shared structural feature necessary to impart the required function of the CAR. As claims 2-14 and 16-23 depend from claim 1, but fail to rectify the lack of descriptive support of the necessary structure of the genus of CARs, they are also rejected.
Claim Rejections - 35 USC § 102
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 1-4, 6-14 and 18-20 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Boyerinas et al., (WO 2018094244; published 5/24/2018).
Boyerinas et al. teaches CAR constructs comprising a TGFβ signal converter, for improved compositions for adoptive T cell therapies and methods for treating cancer (abstract). Boyerinas teaches the immune receptor intracellular signaling domain is an IL-7Ra and an IL2Rg, which is embodiment CTBR7 (pg. 5, lines 4-11). Boyerinas teaches the CAR may comprise an antibody or fragment, which may be an scFv (pg. 70, lines 12-18), and whereby the extracellular domain that binds an antigen selected from the group consisting of CD19, CD20, and EGFR, among others (pg. 70, lines 27-29). Thus, Boyerinas claims a polypeptide comprising a CAR and the signal converter polypeptide of SEQ ID NO: 35, wherein the CAR comprises a binding domain targeting CD19, CD20 or EGFR (pg. 170, claims 112-113). Boyerinas also teaches polynucleotides encoding the polypeptide encoding the CAR construct, vectors comprising the polynucleotides, and cells comprising the polypeptides (pg. 171, claims 115-117); as well as pharmaceutical compositions comprising the polypeptides, vectors, or cells (pg. 172, claim 127). Boyerinas also teaches methods of treating cancer comprising administering the compositions to a subject (pg. 172, claims 129-131).
The polypeptide construct of Boyerinas SEQ ID NO: 35 (i.e. CTBR7) comprises the Hinge and TM (H-TM) sequence of instant SEQ ID NO: 5, the 4-1BB intracellular domain (Y) of instant SEQ ID NO: 6, the CD3zeta domain of instant SEQ ID NO: 7, the IL-7Ra intracellular domain (M) of instant SEQ ID NO: 8, and the IL-2Rg intracellular domain (N) of instant SEQ ID NO: 13, all with 100% amino acid sequence identity. Boyerinas teaches an embodiment of an anti-EGFR CAR and CTBR7 (pg. 143, example 10).
Thus, the anti-EGFR CAR.CTBR7 of Boyerinas, comprises an anti-EGFR antibody scFv (X), a 4-1BB intracellular signaling domain (Y), an IL2Rg intracellular domain (N), as well as a H-TM domain of CD8a, whereby the order would be X-H-TM-Y-CD3zeta-M-N (see Figure 1; CAR.CTBR7). The construct of Boyerinas anticipates instant claims 1-4, 6-14 and 18-20.
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.
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 1-4, 6-14, 16 and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Boyerinas et al., (WO 2018094244; published 5/24/2018).
The reasons why the anti-EGFR CAR.CTBR7 Boyerinas anticipates the construct of instant claims 1-4, 6-14 and 18-20 are described above. However, the anti-EGFR construct of Boyerinas is not an anti-CD20 construct (re. claim 16).
Boyerinas does not reduce to practice a construct comprising a CD20 scFv binding domain (X) on the CAR; however, Boyerinas teaches the antigen binding domain of the receptor binds CD20 (pg. 170, claims 112-113). It would have been obvious to one of skill in the art to modify the anti-EGFR CAR.CTBR7 construct to instead comprise the antigen binding domain targeting CD20. One would have been motivated to do so in order to target the cells expressing the construct to tumor cells expressing CD20, as taught by Boyerinas (see pg. 69, lines 26-27 and pg. 70, lines 27-29). There would have been a reasonable expectation for success given that the tumor-antigen targeting extracellular domain of the CAR construct may be EGFR, CD20 or CD19, whereby each targeting domain is equivalent for its use in the CAR construct as taught by Boyerinas et al. Thus, the anti-CD20 CAR.CTBR7 embodiment of the CAR constructs of Boyerinas make obvious instant claim 16.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Boyerinas et al., (WO 2018094244; published 5/24/2018) as applied to claims 1-4, 6-14, 16 and 18-20 above, and further in view of June et al., (US Patent 9,499,629; issued 11/22/2016).
The reasons why claims 1-4, 6-14, 16 and 18-20 are made obvious by the CAR.CTBR7 constructs of Boyerinas is discussed above. However, while Boyerinas contemplates that an anti-CD19 scFv may be used in the CAR constructs, Boyerinas does not teach wherein the anti-CD19 scFv has the amino acid sequence of instant SEQ ID NO: 2 (re. claim 5).
June et al. claims the use of CAR-T cells to treat cancer (title). The CARs of June comprise a CD19 antigen binding domain, a TM, a costimulatory signaling regions comprising 4-1BB, a CD3zeta signaling domain (col. 91, claim 1); whereby the CD19 binding domain is an antibody or antigen binding fragment, or scFv (col. 93, claims 27-28), wherein the anti-CD19 scFv is SEQ ID NO: 20 (col. 94, claim 43). The anti-CD19 scFv of patent ‘629 SEQ ID NO: 20 is 100% identical to the anti-CD19 scFv of instant SEQ ID NO: 2.
It would have been obvious to one of skill in the art to modify the anti-EGFR CAR.CTBR7 construct to instead comprise the antigen binding domain targeting CD19. One would have been motivated to do so in order to target the cells expressing the construct to tumor cells expressing CD19, as taught by Boyerinas (see pg. 69, lines 26-27 and pg. 70, lines 27-29). There would have been a reasonable expectation for success given that the tumor-antigen targeting extracellular domain of the CAR construct may be EGFR, CD20 or CD19, whereby each targeting domain is equivalent for its use in the CAR construct as taught by Boyerinas et al.; and that June et al. teaches anti-CD19 CAR constructs whereby the extracellular domain of the CAR is the anti-CD19 scFv of SEQ ID NO: 20. Thus, the invention was prima facie obvious to one of skill in the art at the time the invention was made.
Regarding claim 5, June teaches an embodiment of the anti-CD19 scFv for use in the CAR construct, of SEQ ID NO: 20. June SEQ ID NO: 20 is 100% identical to instant SEQ ID NO: 2. Thus, the anti-CD19 CAR constructs of the combination of Boyerinas and June et al. make obvious instant claim 5.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Boyerinas et al., (WO 2018094244; published 5/24/2018) as applied to claims 1-4, 6-14, 16 and 18-20 above, and further in view of Yupo et al., (WO 2017/112877; published 6/29/2017).
The reasons why claims 1-4, 6-14, 16 and 18-20 are made obvious by the CAR.CTBR7 constructs of Boyerinas is discussed above. However, while Boyerinas contemplates that an anti-CD20 scFv may be used in the CAR constructs, Boyerinas does not teach wherein the anti-CD20 scFv has the amino acid sequence of instant SEQ ID NO: 1 (re. claim 22).
Yupo teaches CARs to enhance T cell functions or reduce T cell suppression (abstract). Yupo teaches the CARs comprise an antigen recognition domain, which is selective for or targets an antigen, which may be obtained from any of the wide variety of extracellular domains associated with ligand binding, which may be an scFv, and whereby in specific embodiments, the target antigen is specific for a disease condition, which may be cancer, which has a cell surface antigen, which may be recognized by the chimeric antigen receptor (pg. 16, lines 15-30). Yupo teaches the CAR has an antigen recognition domain, a signal peptide, a hinge region, a TM domain, a co-stimulatory domain and a signaling domain (pg. 35, lines 1-5). Yupo teaches that the antigen recognition domain may target CD20, and may comprise the scFv of SEQ ID NO: 15 (pg. 35, lines 15-16). The anti-CD20 scFv of Yupo SEQ ID NO: 15 is 100% identical to the anti-CD20 scFv of instant SEQ ID NO: 1.
It would have been obvious to one of skill in the art to modify the anti-EGFR CAR.CTBR7 construct to instead comprise the antigen binding domain targeting CD20. One would have been motivated to do so in order to target the cells expressing the construct to tumor cells expressing CD20, as taught by Boyerinas (see pg. 69, lines 26-27 and pg. 70, lines 27-29). There would have been a reasonable expectation for success given that the tumor-antigen targeting extracellular domain of a CAR construct may target EGFR, CD20 or CD19, whereby each targeting domain is equivalent for its use in the CAR construct as taught by Boyerinas et al.; and that Yupo teaches anti-CD20 scFv may be the antigen recognition domain of a CAR construct, and that the scFv of SEQ ID NO: 15 is an example of an anti-CD20 antigen recognition domain. Thus, the invention was prima facie obvious to one of skill in the art at the time the invention was made.
Regarding claim 22, Yupo teaches the anti-CD20 scFv of SEQ ID NO: 15, which is 100% identical to instant SEQ ID NO: 1. Thus, the combination of Boyerinas and Yupo make obvious an anti-CD20 CAR construct whereby the CAR comprises the scFv of instant SEQ ID NO: 1. Therefore, the combination of Boyerinas and Yupo make obvious instant claim 22.
Claim Rejections - 35 USC § 103-Maintained, Amended
This rejection is maintained and amended from the office action of 9/23/2025. Applicants amended the claims to cancel recitation of CLDN18.2, and added new claims 21 and 23 to recite wherein the CAR is specific for CLDN18.2. Thus, the rejection is amended to address the amended claims.
Claims 21 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Yang et al., (US 2021/0169933; published 6/10/2021) and US 2023/0242638 (henceforth US '638) with priority to WO 2021244626; published 9/12/2021.
Claims 21 and 23 recite wherein the X component, comprising a tumor-targeting antibody, is an anti-CLDN18.2 scFv or antibody. As the species of anti-CLDN18.2 scFv or antibody was not previously contemplated in any of the priority documents, the effective filing date for claims 3-5, 8-9 and 14 is 10/19/2022, as described in the Priority section above. While the published US ‘933 application of the applied reference has the same inventors as the instant application, it was published more than one year before the effective filing date for claims 21 and 23, and thus qualifies as prior art under 35 U.S.C. 102 (a)(1) and (a)(2). Further, US ‘638 has priority to WO2021244626. As WO ‘626 was published 9/12/2021, it was published more than one year before the effective filing date and thus qualifies as prior art under 35 U.S.C. 102 (a)(1) and (a)(2). However, the US PGPub ‘638 will be used to cite specific limitations, as it provides an English version of WO2021244626.
US ‘933 teaches chimeric antigen receptors (CAR) having a structure of scFv(X)-(Y)CD3zeta-MN; whereby X is a tumor targeting antibody, Y is an intracellular region of a costimulatory receptor selected from 4-1BB, M is an intracellular region of a gamma chain cytokine receptor selected from IL2Ra or IL7Ra, and N is an intracellular region of IL2Rg (abstract).
Specifically, US ‘933 teaches a CAR wherein the CAR comprises the structure of scFv(X)-(Y)CD3zeta-MN, wherein said scFv(X)-(Y)CD3zeta is SEQ ID NO: 1; wherein M is the intracellular domain of IL7Ra of SEQ ID NO: 2, and wherein N is the intracellular domain of IL2Rg of SEQ ID NO: 7 (pg. 13, claim 4). SEQ ID NO: 1 comprises instant SEQ ID NOs: 1, 5, 6 and 7 with 100% amino acid sequence identity; whereby instant SEQ ID NO: 1 encodes and anti-CD20 scFv, SEQ ID NO: 5 encodes a hinge/transmembrane domain (H-TM), SEQ ID NO: 6 encodes a 4-1BB intracellular domain and SEQ ID NO: 7 encodes a CD3zeta signaling domain. US ‘933 SEQ ID NO: 2, encoding the (M) component, which is the intracellular domain of IL7Ra, is 100% identical to instant SEQ ID NO: 8; and US ‘933 SEQ ID NO: 7, encoding the (N) component, which is the intracellular domain of IL2Rg, is 100% identical to instant SEQ ID NO: 13. Thus, the construct of US ‘933 claim 4, comprises an (anti-CD20scFv)-(H-TM)-(4-1BB)-(CD3z)-(IL7Ra)-(IL2Rg) construct, which is identical to the total construct of instant SEQ ID NO: 16 (of claim 17), which comprises instant SEQ ID NOs: (1)-(5)-(6)-(7)-(8)-(13), respectively.
Further, US ‘933 teaches that X comprises a tumor-targeting antibody or scFv (pg. 2, paras. 0010-0011); and that while X can be an anti-CD19, anti-CD20 or anti-EGFR antibody, X can also be other proteins capable of specifically binding a tumor (pg. 2, para. 0013).
However, US ‘933 does not teach whereby X is an anti-CLDN18.2 antibody or scFv, of instant claims 21 and 23.
US ‘638 teaches CARs targeting CLDN18.2 and uses thereof (title). US ‘638 teaches preparation of anti-CLDN18.2 CAR-T cells (pg. 11, Example 1, para. 0134). US ‘638 teaches that non-synergistic CAR targeting CLDN18.2 were prepared whereby the scFv Ab10, with amino acid sequence of SEQ ID NO: 28, was linked to a hinge region, a transmembrane domain, a 4-1BB costimulatory factor, and a CD3zeta intracellular signaling domain (pg. 11, para. 0134). The anti-CLDN18.2 scFv of amino acid sequence SEQ ID NO: 28 is 100% identical to instant SEQ ID NO: 3, which encodes an anti-CLDN18.2 scFv. Thus, US ‘638 teaches that CARs may be generated whereby the extracellular domain is that of an anti-CLDN18.2 scFv.
It would have been obvious to one of skill in the art to modify the CAR constructs of US ‘933 to comprise an extracellular domain of an anti-CLDN18.2 scFv. One would have been motivated to do so in order to target the cells expression the CAR to a tumor antigen as taught by US ‘933 and by US ‘638. There would have been a reasonable expectation for success given that an anti-CLDN18.2 CAR was generated by US ‘638, comprising the anti-CLDN18.2 scFv of SEQ ID NO: 28, as taught by US ‘638; and that the extracellular scFv of the CAR (i.e. “X”) can be alternative structures such as anti-CD19, anti-CD20 or anti-EGFR scFvs, or also can other proteins capable of specifically binding a tumor, as taught by ‘US 933. Thus the invention was prima facie obvious to one of skill in the art at the time the invention was made.
Regarding claims 21 and 23; the combination of US ‘933 and US ‘638 is described above. Such a combination would encode a CAR with an extracellular domain (X) of the anti-CLDN18.2 scFv of US ‘638 SEQ ID NO: 28, which is identical to instant SEQ ID NO: 3, in combination with an H-TM-Y-CD3zeta-M-N of US ‘933; whereby the H-TM are derived from CD8a (i.e. SEQ ID NO: 5), Y is an intracellular domain of 4-1BB (i.e. SEQ ID NO: 6), M is IL7Ra of (SEQ ID NO: 8), and N is IL2Rg (of SEQ ID NO: 13). Thus, the combination anti-CLDN18.2 CAR of US ‘933 and US ‘638 make obvious instant claims 21 and 23.
Conclusion
No claims are allowed. Claims 1-14 and 16-23 are rejected; claims 15 and 24 are objected to.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642