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 .
Election/Restrictions
Applicant’s election of the species atezolizumab as the PD-L1 inhibitor and pembrolizumab as the PD-1 inhibitor in the reply filed on December 17, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim 44-55 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on December 17, 2025.
Claims 1, 3-5, 11, and 13-15 are under consideration in this office action.
Priority
Acknowledgment is made of applicant's claim for priority under 35 U.S.C. 119(a)-(d) or (f), 365(a) or (b), or 386(a) based upon an application filed in China, CN202010159630.9, on March 9, 2020. The application is the national stage entry of PCT/CN2021/078858.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on September 8, 2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS is being considered by the examiner.
Claim Objections
Claims 1, 4-5, and 14-15 are objected to because of the following informalities:
Claims 1 and 4 use acronyms without first defining what they represent; see “IFN- g” and “CAR-T” in claim 1 and “ICAM-1” in claim 3. While the claims can reference acronyms, the material presented by the acronym must be clearly set forth at the first use of the acronym.
Brain “gliomas” in claim 5 (ln 3) and claim 15 (ln 2) should be the singular “glioma” in order to be consistent with the other cancers listed in the claim.
In claim 14, “enhance killing” should be “enhances killing” in order to correct an error in subject-verb agreement.
In claim 1, the word “wherein” should be included before “the T cell preparation” in line 6 and before “the IFN-g” in line 9.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 15 is rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim does not fall within at least one of the four categories of patent eligible subject matter because a “use”, as recited in the preamble, is not a process, a machine, a manufacture, or a property of matter. Further, the claim does not recite any active, positive steps delimiting how this use is actually practiced. Appropriate correction is required.
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.
Claims 1, 3-5, 11, and 13-15 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.
Claim 1 includes the limitation wherein the IFN-g comprises mutant IFN-g. There is no definition in the claims or specification with respect to what mutations are included, and a person of ordinary skill in the art could not interpret the metes and bounds of this mutant so as to understand how to avoid infringement. It is unclear how the mutation will affect function of IFN-g.
Claim 15 recites a use without any active, positive steps delimiting how this use is actually practiced. Appropriate correction is required.
Claim 15 recites in the preamble “use of claim 11”. Claim 15 depends from claim 11, which does not include a “use” limitation, and there is insufficient antecedent basis for this limitation in the claim.
Claims 3-5, 11, and 13-14, which are dependent on claim 1, are also rejected for failing to cure the indefiniteness of the base claim.
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 1, 3-5, 11, and 13-15 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.
“[T]he 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.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
Claims 1, 5, 11, 13, and 15 are directed to a method of treating a patient with a tumor by administering a CAR-T cell preparation, wherein the CAR-T cell targets a tumor-specific antigen. The antigen-binding domain of the CAR is not sufficiently described to meet the written description requirement. The CAR of the claim is only defined by its function, i.e. what it binds. Furthermore, as the claims are not directed to a specific tumor antigen, the antigen-binding domain of the CAR could read on any number of antibodies that bind tumor-specific antigens. As such, the claims encompass a vast genus of antigen-binding domains that bind a tumor-specific antigen.
Although dependent claims 3-4 and 14 do require specific function (i.e. sensitizing the tumor cell, upregulating ICAM-1, and enhancing the killing effect), there is still no clear structure/function correlation since independent claims 1 and 11 are provide no support regarding what is the actual structure requirement for the claimed antigen-binding domain of the CAR.
Antibodies generally share certain characteristics such as Fc regions or hinge regions. However, these structures are not correlated with the binding function of the antibody. It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three complementarity determining regions (CDRs) that provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences, which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (see Almagro et al, Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1; PTO-892).
There is no way to a priori look at an antigen sequence and envisage the combination of six CDRs that will bind that antigen. First, even highly related CDRs may not bind the same target. See for example Kussie (instant PTO-892), who demonstrates that a single amino acid change in the heavy chain of an antibody that binds p-azophenylarsonate (Ars) completely abrogates the ability of the antibody to bind Ars but adds the functionality of binding the structurally related p-azophenylsulfonate (see abstract). Second, even when provided with several related antibodies that bind the desired target, this does not represent the astronomical and potentially unknowable breadth of all possible amino acid sequences which will result in the desired binding properties. This is exemplified by the Court decision in Abbvie (Abbvie v Janssen 759 F.3d 1285 (Fed. Cir. 2014)), where Abbvie developed over 200 antibodies that shared 99.5% identity in the variable regions (pg 7) and which bound the target, but in no way allowed one to envisage the unique structure of Centocor’s antibodies which bound the same target but shared only 50% sequence similarity (see table on pg 11).
While the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains.
According to the specification, the applicant has disclosed various antigen-binding domains for the CAR, which are known in the art and are comprised of specific combinations of heavy chain CDRs and light chain CDRs. However, the specification does not provide adequate written description for the entire claimed genus of CARs that target tumor-specific antigen, because one skilled in the art would be unable to immediately envision, recognize, or distinguish most of the members comprised within the genus claimed, specifically which heavy chain and light chain amino acid sequences should be combined to yield an antigen-binding region that is capable of binding the target.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.
In the instant case, the specification provides insufficient direction or guidance concerning the relationship between the structure of the possible antibody to demonstrate possession of the breadth of the genus of antibodies encompassed by the instant claims, especially in view of the unpredictability of such an endeavor. The prior art, as evidenced by Edwards et al., 2003 (instant PTO-892), teaches there is a substantially huge antibody diversity produced to one single antigen target. Edwards provides evidence that over 1000 antibodies, all different amino acid sequences, were generated towards one single protein antigen target (see abstract). Without a correlation between structure and function, the claims do little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Applicant has not described the claimed invention sufficiently to show they had possession of the claimed genus of antibodies that bind tumor-specific antigen. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester v. G.D. Searle & Co., 358 F.3d 916, 69 USPQ2d 1886 (Fed. Cir. 2004).
To provide adequate written description and evidence of possession of the claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In the instant case, the only factors present in the claims are a recitation of one generic, broad genus that encompassed a diverse and huge number of possible antibodies and other agents that bind the disclosed epitope. The specification does not provide a consistent structure for all of the possible antibodies and fails to provide a representative number of species for the claimed genus. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only several species within the genus.
For claims drawn to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). 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 the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding), “[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011). An antibody described only by functional characteristic, such as antibody that binds a tumor antigen, without any known or disclosed correlation between that function and the structure of the sequence, is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the biomolecule of interest. In re Bell, 991 F.2d 781, 26 U.S.P.Q.2d 1529 (Fed. Cir. 1993). In re Deuel, 51 F.3d 1552, 34 U.S.P.Q.2d 1210 (Fed. Cir. 1995).
With the exception of specifically disclosed antibodies with specific CDRs, the skilled artisan cannot envision the detailed chemical structure of all of the encompassed antibodies, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The product itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Therefore, claims 1, 3-5, 11, and 13-15 do not meet the written description requirement.
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, 3-5, 11, and 13-15 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by US 20160361360A1, published December 15, 2016 (“Chang”; instant PTO-892).
The claims are directed to a method of treating cancer by administering IFN-g and a CAR-T cell preparation that target a tumor-specific antigen.
Chang teaches compositions comprising CAR-T constructs [0011] and methods for the treatment of cancer in a subject [0182]. The targeting domain of the CAR-T construct may be directed to the tumor-specific antigen HER2 [0020], which meets the limitation of instant claim 1 directed to a CAR-T cell preparation that targets a tumor specific antigen. The CAR-T cell therapy of Chang may be combined with one or more other immunomodulators to enhance the immune response, including interferon-g, which reads on the interferon-g limitation of instant claim 1.
Chang teaches that the CAR-T therapy may be used for treating ovarian cancer, breast cancer, glioma, colorectal cancer, renal cancer, liver cancer, lung cancer, melanoma, and bladder cancer ([0026],[0193]), which reads on instant claims 5 and 15.
Further, Chang teaches that immune checkpoint inhibitors may be used in combination with the CAR-T cell therapy [0024], including the anti-PD1 antibody MK-3475 [0084] and the anti-PD-L1 antibody MPDL3280A ([0086],[0192]). While Chang does not provide alternate names for MK-3475 and MPDL3280A, it is known in the art that pembrolizumab is MK-3475 (pg 12, column 1, para 4) and atezolizumab is MPDL3280A (pg 11, column 2, para 3), as evidenced by Massari et al (instant PTO-892). Therefore, Chang teaches the limitations of claims 11 and 13 directed to PD0L1 inhibitor atezolizumab and the PD-1 inhibitor pembrolizumab.
While Chang is silent regarding the method sensitizing the tumor cell, upregulating ICAM-1, and enhancing the killing effect of claims 3-4 and 14, it is clear that the same composition would have the same characteristics and effects as the instantly claimed composition since there is no evidence to the contrary. Note that rejections for anticipation are appropriate when the prior art discloses a method (or product) that appears to be identical except that the art is silent as to an inherent property; see MPEP § 2112(III). In such situations, the burden is on applicant to provide evidence that the prior art product (or method) is not the same.
Chang anticipates claims 1, 3-4, and 11-5.
Conclusion
No claim is allowed.
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Jennifer Benavides
Examiner
Art Unit 1675
/JENNIFER A BENAVIDES/Examiner, Art Unit 1675