DETAILED ACTION
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 preliminary amendments received December 16, 2024 are acknowledged.
Claims 8-15, 28, and 30-40 have been canceled.
Claims 2-7, 16, 19-24, 26, 27, and 29 have been amended.
Claims 1-7, 16-27 and 29 are pending in the instant application.
Information Disclosure Statement
The IDS form received 8/1/2024 is acknowledged and the references cited therein have been considered.
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.
Claims 1-5, 7, 16-20, and 22 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of a naturally occurring product without significantly more. The claim(s) recite(s) a T cell receptor comprising alpha and beta chains which are defined by the presence of one or more polypeptide sequences identified via SEQ ID numbers, as well as nucleic acids encoding such polypeptides and host cells expressing such polypeptides. This judicial exception is not integrated into a practical application because the specification discloses that applicant isolated a T cell from a patient via single cell cloning (i.e. clone 24), sequenced the T cell receptor, and that T cell receptor had the biological sequences of SEQ ID NOs:31 and 32 which comprise the CDR sequences of SEQ ID NOs:12-14 and 6-8 respectively (see particularly example 2 and Tables 1 and 7) . The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there is no requirement for any specific structural element which necessarily makes the claimed polypeptide, polynucleotide or cell different from that which is found in nature (i.e. the naturally occurring product which is the T cell named clone 24 which was single cell cloned from a human patient by applicant). It is noted that claim recites “engineered” T cell receptor, but inspection of the specification does not reveal any meaning for this term that would necessitate a structure that is different from what occurs naturally. Note this is in contrast to claim 6 (which is not part of this rejection) which recites a fusion protein by SEQ ID number that joins naturally occurring sequences in a manner that is decidedly non-natural. Applicant is remined that a product is limited by the structure of what it is, rather than how it was made, and thus recitation of “engineered” without any structural limitations attached (such as by way of definition in the specification or explicit structural limitation in the claim itself) can very reasonably be seen as a product by process type limitation which does not provide patentable distinctiveness absent a necessary change in structure over what was previously known. See MPEP 2113. Also note that if any embodiment of a claimed invention encompasses a naturally occurring product, the claim is not patentable absent amendment to exclude the naturally occurring material.
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Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-7, 16-27 and 29 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 1 is drawn to an “engineered” T cell receptor which binds an epitope of splicing factor SF3B1, comprises alpha and beta chain variable regions and has at least one CDR in the alpha and beta chains defined by SEQ ID number. Dependent claims add additional limitations such as additional sequence including the full length alpha and beta variable domains, nucleic acids encoding such receptors, and cells expressing such receptors. Applicant has also presented independent claim 29, which is a method of treating SF3B1K700E positive cancers by administering cells expressing the T cell receptor which has the same limitations as presented in claim 1.
The specification discloses identifying a mutation in a splicing factor that is present in some hematopoietic cancers and can be presented to the immune system in a restricting element such that T cells of the immune system can discriminate between the mutant and wild type versions of the splicing factor, with applicant’s goal being to selectively kill cells expressing the mutant but not the wild type epitope (see for example pages 1-3 as well as example 1). Applicant then single cell cloned a T cell from a patient that responded to stimulation with the peptide-MHC complex of SEQ NO:1-HLA-B*40:01 (example 2) and demonstrated that cells expressing the cloned TCR could kill targets expressing the peptide-MHC complex of SEQ NO:1-HLA-B*40:01 in vitro (example 5). Notably, no data concerning CDR mutagenesis and its impact on peptide-MHC binding and target killing appears to be disclosed.
As such, the instant specification provides insufficient direction or guidance for the skilled artisan to make and use the breadth of binding proteins encompassed by the instant claims.
The skilled artisan expects both Vα and Vβ are required to create the TCR peptide-MHC binding site (see Janeway et al., Immunobiology, 5th Ed., Garland Science, pages 106-108 and 260-263, (2001)). In particular, the art teaches the peptide is predominately recognized by the TCR CDR3s while the TCR CDR1 and 2 regions are predominately involved in MHC binding. Notably, while this division of binding activity between CDRs 1-2 and 3 generally holds true this does not mean that the CDR3 regions are always exclusively responsible for interacting directly with the peptide. Indeed, in some instances CDR1 and CDR2 residues have been shown to directly bind peptide (see, e.g., Manning et al., Immunity, Vol. 8, 413-425, April, 1998, in particular Conclusions section on page 423). However, the prior art provides the skilled artisan with insufficient guidance or direction as to which particular CDR residues are required for MHC or peptide binding, or which CDR and/or TCR framework residues are required to bring about the canonical diagonal interaction of the TCR with peptide-bound MHC (see, e.g., Garcia et al., Cell, Vol. 122, 333–336, August 12, 2005, especially page 333, right col., 1st-3rd paragraphs; page 336, col. bridging paragraph through right col., 1st paragraph and Figure 1, cited herewith). Indeed, one hypothesis in the art is that the CDR1 and 2 interactions with the MHC are dependent on the CDR3 interaction with the peptide bound to the MHC, and, if so, "there may be as many TCR/pMHC orientations as CDR3 sequences.” (see Garcia page 336, col. bridging paragraph).
It should be noted that as per claim 1, only 2 CDRs are of fixed sequence, one in the alpha and one in the beta, which means that the remaining CDRs reasonably are random sequence. As discussed above, artisans reasonably expect that all six CDR are needed to interact with the peptide-MHC complex and thus extensive trial and error research and experimentation would need to be performed in order to make constructs comprising fewer than 6 fully defined CDRs that maintained binding activity. Note that claims reciting percent identity to variable alpha and beta chains (such as in claims 4 and 5 or the “scFv-like” fusion protein of claim 6) allow for totally random CDR mutations in 4 out of the 6 CDRs and thus such additional limitations fail to remedy the deficiencies of independent claim 1. Further, as discussed above the art recognizes that in general T cell receptors bind a peptide-MHC complex, yet claim 1 appear to recite that the claimed T cell receptor can bind SF3B1 in the absence of any restricting element. Data supporting that the TCR of clone 24 (i.e. that isolated from a human in example 2 and subsequently sequenced) binds peptide in the absence of an HLA-B*40:01 restricting element, or binds a random peptide from somewhere in SF3B1 that does not comprise the K700E mutation, has not been presented. Thus while artisans could reasonably make and use TCR that comprise all of the CDRs of claim 1 which bind the peptide of SEQ ID NO:1 when presented by HLA-B*40:01 (and therefore nucleic acids encoding and host cells expressing same) based upon the guidance and direction of the specification, artisans would be unable make and use the full extent of that which applicant has claimed.
Therefore, in view of the quantity of experimentation necessary, the limited working examples, the unpredictability of the art, the lack of sufficient guidance in the specification, and the breadth of the claims, it would take undue trials and errors to practice the inventions as presently claimed.
Claims 1-7, 16-27 and 29 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 claims contain 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 inventors, at the time the application was filed, had possession of the claimed invention.
Applicant has broadly claimed “engineered” T cell receptors, nucleic acids encoding such receptors, and cells expressing such receptors which have the functional property of binding “SF3B1K700E, an epitope of SF3B1K700E , or an SF3B1K700E epitope/human leukocyte antigen (HLA) complex”. Such TCR are required to have an alpha and beta chain variable domain, and within said domains at least one of the three CDRs are fixed in sequence via specific SEQ ID numbers. Note that while the impendent claims recite six CDRs, 3 for each chain, as written each chain only need have one of its respective three sequences to meet the recited structural limitations. To support such breadth the specification discloses single cell cloning and sequencing a TCR that binds the peptide-MHC complex of SEQ NO:1-HLA-B*40:01 (i.e. clone 24, see most particularly example 2). The specification does not appear to disclose any data concerning CDR mutagenesis or the impact of mutagenesis upon peptide-MHC binding and target killing.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., 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 applicant was in possession of the genus. See MPEP 2163. In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted: “A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin [e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.” The court has further stated that “Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Id. at 1566, 43 USPQ2d at 1404 (quoting Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606). Also see Enzo-Biochem v. Gen-Probe 01-1230 (CAFC 2002). Recent court cases have emphasized the need for correlation between a well-defined structure and recited functional limitations. For example, the courts have indicated that recitation of an antibody which has specific functional properties in the absence of knowledge of the antibody sequences that give rise to said functional properties do not satisfy the requirements for written description. See for example AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014). Such cases have indicated that that it is improper to allow patentees to claim antibodies by describing something that is not the invention, i.e. the antigen, as knowledge of the chemical structure of an antigen does not provide information as to what a structure binding that antigen necessarily looks like (i.e. the primary amino acid structure of the antibody). Applicant is reminded that the courts have long ruled that “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, 358 F.3d at 927, 69 USPQ2d at 1895. As such, disclosure of a screening assay to test for functional properties of an antibody does not provide evidence of possession of the antibody itself. Further, courts have long ruled that “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.” See Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005). Also, “A sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus.” See AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69.
As has been long known by the skilled artisan, antibodies and TCRs have structural and functional similarities. For example, both molecules are heterodimers based on the characteristic immunoglobulin fold, genes encoding both molecules are constructed via V(D)J recombination of germline encoded nucleic acids, both molecules rely on accessory molecules to promote signal transduction upon ligand binding. Indeed, the skilled artisan expects both Vα and Vβ are required to create the TCR peptide-MHC binding site (see Janeway et al., Immunobiology, 5th Ed., Garland Science, pages 106-108 and 260-263, (2001)). In particular, the art teaches the peptide is predominately recognized by the TCR CDR3s while the TCR CDR1 and 2 regions are predominately involved in MHC binding. Notably, while this division of binding activity between CDRs 1-2 and 3 generally holds true this does not mean that the CDR3 regions are always exclusively responsible for interacting directly with the peptide. Indeed, in some instances CDR1 and CDR2 residues have been shown to directly bind peptide (see, e.g., Manning et al., Immunity, Vol. 8, 413-425, April, 1998, in particular Conclusions section on page 423). However, the prior art provides the skilled artisan with insufficient guidance or direction as to which particular CDR residues are required for MHC or peptide binding, or which CDR and/or TCR framework residues are required to bring about the canonical diagonal interaction of the TCR with peptide-bound MHC (see, e.g., Garcia et al., Cell, Vol. 122, 333–336, August 12, 2005, especially page 333, right col., 1st-3rd paragraphs; page 336, col. bridging paragraph through right col., 1st paragraph and Figure 1, cited herewith). Indeed, one hypothesis in the art is that the CDR1 and 2 interactions with the MHC are dependent on the CDR3 interaction with the peptide bound to the MHC, and, if so, "there may be as many TCR/pMHC orientations as CDR3 sequences.” (see Garcia page 336, col. bridging paragraph). Thus, the art clearly establishes that it is the structure of three TCR CDRs which give rise to the function of binding a peptide-MHC complex, just as six CDRs are generally accepted in the art for antibody-antigen interactions.
To illustrate this point more concretely, Sollid et al. (WO 2019/180271) disclose TCR that comprise significantly more than one identical CDR on each chain yet are disclosed as being celiac antigens rather than the peptide-MHC complex of SEQ NO:1-HLA-B*40:01 as recited in for example instant clam 3 (see entire document and the enclosed sequence alignments). Thus it appears quite clear that the amount of structure recited as necessarily being present in the claims as presently constructed is not reasonably correlated with the function of binding a specific peptide-MHC complex. Additionally, a TCR reasonably only binds peptide in the context of a restricting MHC molecule (i.e. one that the peptide can bind as structural constraints govern which MHC can and cannot bind any given peptide sequence) based upon the art, and applicant has provided no evidence that TCR binding occurs in the absence of MHC presentation (e.g. free peptide in solution) even though by reciting binding “SF3B1K700E, an epitope of SF3B1K700E , or an SF3B1K700E epitope/human leukocyte antigen (HLA) complex” in claim 1 applicant has done just that.
Additionally, claim 1 recites that the claimed TCR has been “engineered” yet the specification does not appear to define this term in any way that would necessarily add identifying structural features or limitations to that which is claimed, and the claim itself does not recite any additional structural features which must be present that would serve to distinguish that which is claimed from that which is obtained from nature, such as T cell clone 24 which was isolated from a human patient by applicant as disclosed in working example 2. Thus it does not appear that this claim term provides for any clearly identifiable structural or functional properties that add more than the recitation of TCR CDR sequences as discussed above.
Therefore, in view of the breadth of the claims artisans would reasonably conclude that while applicant was in possession of clone 24 which encompasses the polypeptide sequences for its TCR which binds the peptide-MHC complex of SEQ NO:1-HLA-B*40:01, polynucleotides encoding said TCR, and cells expressing said TCR, applicant was not in possession of the full breadth TCR, polynucleotides, and cells comprising TCR defined using less than 6 non-degenerate polypeptide sequences, 3 for the alpha and 3 for the beta variable domains. Amendment of the claims to minimally require that TCR comprise six fully defined CDRs and recite that such a TCR binds the peptide-MHC complex of SEQ NO:1-HLA-B*40:01 is the most straightforward way to address most of the issues discussed above.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-5, 16-20, and 22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sollid et al. (WO 2019/180271).
Sollid et al. disclose the isolation of T cells from patents and single cell sequencing their TCRs, with constructs comprising 96.5% identity to SEQ ID NOs:31 and 32 (and thus comprising 100% identity to SEQ ID NOs:6, 7, 12, and 13) being disclosed (see entire document, particularly the abstract, claims, page 40 and enclosed sequence alignments).
It is noted that Sollid et al. do not disclose that their TCR bind SF3B1. However, and evidenced by the enclosed sequence alignments, the TCR comprise more than the minimum amount of specific structure required by instant independent claim 1. Applicant is reminded that as the courts have long ruled, "Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id. Since the products of Sollid et al. comprise the structure recited in the claims, functional properties, even if not disclosed, are necessarily present. This is because the prior art teaches the structure recited in the instant claims as giving rise to the recited functional properties. Note similarly that the T cells subjected to sequencing by Sollid et al. necessarily expressed the TCR in question and thus are a “host cell” for the expressed polypeptide. Additionally, while claim 1 recites that the claimed TCR is “engineered” there is no limiting definition for this term in the specification nor is there any specific structure recited in claim 1 which would preclude the naturally occurring T cells and receptors of Sollid et al from reading upon the structures of that which has been presently claimed. Therefore the prior art anticipates the instant claimed inventions.
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Michael Szperka whose telephone number is (571)272-2934. The examiner can normally be reached Monday-Friday 8:30-5:00.
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Michael Szperka
Primary Examiner
Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641
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