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 .
Status of the Claims
Claims 1-60 have been previously canceled. Claims 61-81 are pending and examined on the merits.
Priority
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. The instant application claims domestic benefit from U.S. provisional application 63/149952 filed on February 16, 2021.
Information Disclosure Statement
An Information Disclosure Statement (IDS) has not been filed with the instant application.
Applicant is reminded that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Objections to the Specification
The disclosure is objected to because of the following informalities: Para [0035] references Fig. 4 as depicting activation of Jurkat cells co-expressing HLA-A*02 blocker and HER2 CAR1 activator, the construct labeled CT299. Fig. 4 is labeled as depicting cells co-expressing the HER2 CAR4 activator, which Fig. 1 indicates is the construct labeled CT298
Appropriate correction is required.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code in Para. [0598]. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the term Nucleofector, Neon, One-Step, Tecan Infinite (Para. [0584]), Allcells, TransAct, and AutoMACS (Para. [0589]), which are trade names or a marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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 66 is 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 66, which depends from claim 61, recites the limitation "the scFv" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 61 has two recitations of an scFv – one in line 7 in reference to the scFv of the extracellular ligand binding domain of the activator receptor and one in line 16 in reference to the scFv of the extracellular ligand binding domain of the inhibitory receptor. As instantly claimed, it is unclear which scFv claim 66 is intended to further limit. Appropriate correction is required.
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 61-81 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 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 inventors, at the time the application was filed, had possession of the claimed invention.
Independent claims 61 and 77, encompass a genus of T cells responsive to loss of heterozygosity at an HLA-A*03 allele in a cancer cell, comprising:
a genus of activator receptors comprising polypeptide sequences at least 80% identical to SEQ ID NO: 291 having an extracellular ligand binding domain specific to an erb-b2 receptor tyrosine kinase 2 (HER2) antigen comprising an scFv comprising a heavy chain variable (VH) region comprising complement determining regions (CDRs) CDR-H1 of SEQ ID NO: 36, CDR-H2 of SEQ ID NO: 38, and CDR-H3 of SEQ ID NO: 41; and a light chain variable region (VL) comprising CDRs CDR-L1 of SEQ ID NO: 30, CDR-L2 of SEQ ID NO: 32, and CDR-L3 of SEQ ID NO: 34 or polynucleotide sequences at least 80% identical to SEQ ID NO: 292 encoding said activator receptor and
a genus of inhibitory receptors comprising polypeptide sequences at least 80% identical to SEQ ID NO: 305 having an extracellular ligand binding domain specific to an HLA-A*03 allele of HLA-A comprising an scFv comprising a VH region comprising CDRs CDR-H1 of SEQ ID NO: 95, CDR-H2 of SEQ ID NO: 98, and CDR-H3 of SEQ ID NO: 101; and a VL region comprising CDRs CDR-L1 of SEQ ID NO: 87, CDR-L2 of SEQ ID NO: 90 or SEQ ID NO: 91, and CDR-L3 of SEQ ID NO: 92 or polynucleotide sequences at least 80% identical to SEQ ID NO: 306 encoding said inhibitory receptor,
Independent claim 74, encompasses a genus of polynucleotide systems comprising a genus of polynucleotide sequences encoding a) a genus of activator receptors comprising polypeptide sequences at least 80% identical to SEQ ID NO: 291 having an extracellular ligand binding domain specific to a HER2 antigen comprising an scFv comprising VH and VL regions comprising SEQ ID NOs: 36, 38, 41, 30, 32, and 34 and a b) genus of polynucleotide sequences encoding a genus of inhibitory receptors comprising polypeptide sequences at least 80% identical to SEQ ID NO: 305 having an extracellular ligand binding domain specific to an HLA-A*03 allele comprising an scFv comprising VH and VL regions comprising SEQ ID NOs: 95, 98, 101, 87, 90 or 91, 92.
Dependent claims 62 and 78 encompass a genus of T cells responsive to loss of heterozygosity at an HLA-A*03 allele where the T cell is activated in the presence of a cancer cell.
Dependent claims 63-65 and 79-81 encompass a genus of types of T cells of independent claims 61 and 77 respectively.
Dependent claim 66 encompasses a genus T cells comprising a genus of scFvs comprising a sequence having at least 97% identity to SEQ ID NO: 51.
Dependent claims 67-69 encompass a genus of activator receptors within the T cells which are CARs and a genus of structural elements of the CARs.
Dependent claim 70 encompasses a genus of inhibitory receptors within the T cells comprising LILRB1 structural elements.
Dependent claims 71 and 72 encompass a genus of functional effects of the genus of T cells of independent claim 61.
Dependent claim 73 encompasses a genus of pharmaceutical compositions comprising the genus of T cells of independent claim 61.
Dependent claim 75 encompasses a genus of vectors comprising the genus of polynucleotide systems of independent claim 74.
Dependent claim 76, encompasses a genus of methods of treating a HER2+ cancer in a genus of subjects having or suspected of having a loss of heterozygosity at an HLA-A*03 allele comprising administration of the genus of T cells of claim 61.
Under the new Written Description Guidelines for antigen binding protein molecules, the Examiner is directed to determine whether one skilled in the art would recognize that the applicant was in possession of the claimed invention as a whole at the time of filing. The following considerations are critical to this determination: on 22 February 2018, the USPTO provided a Memorandum clarifying the Written Description Guidelines for claims drawn to antibodies, which can be found at www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf. That Memorandum indicates that, in compliance with recent legal decisions, the disclosure of a fully characterized antigen no longer is sufficient written description of an antibody to that antigen. Accordingly, the instant claims have been re-evaluated in view of that guidance.
“[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.
ACTUAL REDUCTION TO PRACTICE
With regard to claims 61 and 77, encompassing a genus T cells responsive to loss of heterozygosity at an HLA-A *03 allele in a cancer cell comprising a) activator receptors specific to a HER2 antigen encompassed by polypeptide sequences at least 80% identical to SEQ ID NO: 291 comprising an scFv comprising SEQ ID NOs: 30, 32, 34, 36, 38, and 41 (and the associated polynucleotide sequences at least 80% identical to SEQ ID NO: 292 encoding the activator receptor polypeptide); and b) inhibitor receptors specific to an HLA-A *03 allele encompassed by polypeptide sequences at least 80% identical to SEQ ID NO: 305 comprising an scFv comprising SEQ ID NOs: 87, 90 or 91, 92, 95, 98, and 101 (and the associated polynucleotide sequences at least 80% identical to SEQ ID NO: 306 encoding the inhibitor receptor polypeptide), the specification details a single embodiment of a) an activator receptor which can bind to a HER2 antigen comprising a polypeptide sequence at least 80% identical to SEQ ID NO: 291, CT292, and the associated polynucleotide encoding the activator receptor SEQ ID NO: 292 (See Tables 3, 4, and 25) and b) a single embodiment for the inhibitor receptor comprising the claimed polypeptide sequence at least 80% identical to SEQ ID NO: 305 (and polynucleotide sequence at least 80% identical to SEQ ID NO: 306 encoding SEQ ID NO: 305) which comprises CDRS represented by SEQ ID NOs: 87, 90 or 91, 92, 95, 98, and 101 (See Tables 8 and 26). It appears from the disclosure that the instantly claimed inhibitor receptors represented by SEQ ID NOs: 305 comprise a binding domains specific to HLA-A *02 (See Tables 8 and 26).
Based on Applicant’s specification, Applicant has reduced to practice a single disclosed SEQ ID NO: encoding an inhibitory receptor having binding specificity for HLA-A *03, SEQ ID NO: 405, in conjunction with a HER2 activator receptor having SEQ ID NO: 291 (CT292/CAR1) which was able inhibit activation of the HER2 CAR (See Tables 7 and 9, Example 13, and Fig. 26A).
With regard to independent claim 74, encompassing a genus of polynucleotide systems comprising a genus of polynucleotide sequences encoding a genus of activator receptors comprising polypeptide sequences at least 80% identical to SEQ ID NO: 291 having an extracellular ligand binding domain specific to a HER2 antigen comprising an scFv comprising VH and VL regions comprising SEQ ID NOs: 36, 38, 41, 30, 32, and 34 and a genus of polynucleotide sequences encoding a genus of inhibitory receptors comprising polypeptide sequences at least 80% identical to SEQ ID NO: 305 having an extracellular ligand binding domain specific to an HLA-A*03 allele comprising an scFv comprising VH and VL regions comprising SEQ ID NOs: 95, 98, 101, 87, 90 or 91, 92. As detailed above, Applicant has reduced to practice a single disclosed SEQ ID NO: encoding an inhibitory receptor having binding specificity for HLA-A *03, SEQ ID NO: 405, in conjunction with a HER2 activator receptor having SEQ ID NO: 291 (CT292/CAR1) which was able inhibit activation of the HER2 CAR (See Example 13 and Fig. 26A).
Dependent claims 62 and 78 encompass activation of the genus of T cells responsive to loss of heterozygosity at an HLA-A*03 allele in the presence of a cancer cell. As stated above, Applicant discloses a fixed number of T cells comprising a fixed number of SEQ ID NOs encoding activating and inhibitory receptors.
Dependent claims 63-65 and 79-81 encompass a genus of types of T cells of independent claims 61 and 77 respectively. Applicant has disclosed working embodiments using Jurkat cells (see Examples 2-3, 7, and 13 which are considered to be CD 8-, CD4+) and “primary T cells” (see Examples 4-6, 8) however, Applicant does not define what is considered primary T cells.
With regard to dependent claim 66 encompasses a genus of T cells comprising scFvs comprising a sequence having at least 97% identity to SEQ ID NO: 51. As stated above, Applicant discloses a fixed number of T cells comprising a fixed number of SEQ ID NOs encoding activating and inhibitory receptors which comprise specific scFv SEQ ID NOs.
With regard to dependent claims 67-69 encompass a genus of activator receptors within the T cells which are CARs and a genus of structural elements of the CARs comprising a CD8 hinge, a transmembrane domain from CD8 of CD28, and intracellular domains comprising CD28, 4-1BB, and CD3z.
With regard to dependent claim 70 encompasses a genus of inhibitory receptors within the T cells comprising LILRB1 hinge and transmembrane domains.
With regard to dependent claims 71 and 72 encompass a genus of functional effects of the genus of T cells of independent claim 61. As stated above, Applicant discloses a fixed number of T cells comprising a fixed number of SEQ ID NOs encoding activating and inhibitory receptors.
With regard to dependent claim 73 encompasses a genus of pharmaceutical compositions comprising the genus of T cells of independent claim 61. As stated above, Applicant discloses a fixed number of T cells comprising a fixed number of SEQ ID NOs encoding activating and inhibitory receptors.
With regard to dependent claim 75 encompasses a genus of vectors comprising the genus of polynucleotide systems of independent claim 74. As stated above, Applicant discloses a fixed number of polynucleotide systems comprising a fixed number of SEQ ID NOs encoding activating and inhibitory receptors.
With regard to dependent claim 76, encompasses a genus of methods of treating a HER2+ cancer in a genus of subjects having or suspected of having a loss of heterozygosity at an HLA-A*03 allele comprising administration of the genus of T cells of claim 61. As stated above, Applicant discloses a fixed number of T cells comprising a fixed number of SEQ ID NOs encoding activating and inhibitory receptors.
Therefore, as detailed above, Applicant was only in possession of a limited number of SEQ ID NOs encoding a HER2 specific activating receptor and a HLA-A *03 specific inhibitory receptor and the associated T cells and polynucleotides encompassing those specific SEQ ID NOs.
DISCLOSURE OF STRUCTURE
The Applicant has provided sequence listings of SEQ ID NOs for a single embodiment of the HER2 specific activator receptor comprising 80% identity to SEQ ID NO: 291 (and polynucleotide SEQ ID NO: 292) comprising CDRs having SEQ ID NOs: 30, 32, 34, 36, 38, and 41 and a single embodiment of inhibitory receptor comprising 80% identity to SEQ ID NO: 305 (and polynucleotide SEQ ID NO: 306) comprising CDRs having SEQ ID NOs: 87, 90 or 91, 92, 95, 98, and 101, however, the disclosed inhibitory receptor appears to be specific to HLA-A *02 and not to HLA-A *03. Certainly, with the help of a computer, a skilled artisan could identify the specific sequences which could function as HER2 specific activator receptors and/or HLA-A *03 specific inhibitory receptors. However, neither the specification nor the art indicate a relationship between the structure of the claimed genus of instantly claimed SEQ ID NOs and the ability to produce functional HER2 specific activator receptors and/or HLA-A *03 specific inhibitory receptors.
As detailed above, Applicant has reduced to practice SEQ ID NO: 405 as encoding an inhibitory receptor specific to an HLA-A *03 allele. However, SEQ ID NO: 405 is not at least 80% identical to instantly claimed SEQ ID NO: 305 which encodes the inhibitory receptor binding to an HLA-A *03 allele.
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Further, SEQ ID NO: 405 comprises CDRs as outlined in Table 9 which details exemplary SEQ ID NOs for HLA-A *03-specific CDR ligand binding domains. It is noted that the instantly claimed CDRs comprised by the instantly claimed inhibitory receptor sequence (i.e., SEQ ID NOs: 87, 90 or 91, 92, 95, 98, and 101) can be found in Table 8 of the instant specification which are disclosed as CDRs specific to HLA-A *02.
SUFFICIENT RELEVANT IDENTIFYING CHARACTERISTICS
As mentioned in above, sequences corresponding to a single HER2 specific activator receptor, a single HLA-A *02 inhibitory receptor, as well as a single HLA-A *03 inhibitory receptor have been provided.
Accordingly, if the skilled artisan sought to generate the claimed genus of T cells and polynucleotide systems comprising a) a HER2 specific activating receptor comprising a polypeptide sequence at least 80% identical to SEQ ID NO: 291 and/or a polynucleotide sequence which encodes the inhibitory receptor having at least 80% identical to SEQ ID NO: 292 and b) an HLA-A *03 specific an inhibitory receptor comprising a polypeptide sequence at least 80% identical to SEQ ID NO: 305 and/or a polynucleotide sequence which encodes the inhibitory receptor having at least 80% identical to SEQ ID NO: 306, they would first need to know which sequences encoding the inhibitory receptor could be chosen and still be able to predictably produce an inhibitory receptor capable of binding to an HLA-A *03 allele.
First, SEQ ID NO: 291 is 552 amino acids and SEQ ID NO: 305 is 522 amino. Applicant’s recitation of 80% identity to SEQ ID NOs: 291 and 305 encompasses receptor variants that contain up to 20% variation within the instantly claimed sequences, corresponding to substitution of 110 or 104 amino acids, respectively, provided that the variant sequences comprise the instantly claimed CDRs. As instantly claimed, more than 100 amino acids in each sequence could be substituted with any of the other 19 possible amino acids at any position outside of the instantly claimed CDRs which results in a very large number of variant polypeptides. For a polypeptide comprising 100 residues, a single amino substitution by each of the other 19 amino acids results in 1,900 variant polypeptides. Substitution of 20 amino acids (i.e., 80% identity) results in approximately 190020 variant polypeptides. Thus, the scope of the claims encompasses a large number of variant polypeptides of activator receptors which retain the functional ability to bind to HER2 and of inhibitory receptors which retain the functional ability to bind to HLA-A*03.
Second, regarding the HLA-A specific inhibitory receptor, although the instant specification has reduced to practice the instantly claimed inhibitory receptors as capable of binding to HLA-A *02, the specification does not provide any guidance as to whether the instantly claimed inhibitor receptors comprising 80% identity to SEQ ID NOs: 305 or 306 would be capable of binding to HLA-A *03. Based on Applicant’s instant specification, SEQ ID NOs: 305 (and associated polynucleotide SEQ ID NO: 306) comprises the claimed CDRs and encodes an inhibitory receptor capable of binding to HLA-A *02 (See Table 26) and the instantly claimed VH and VL regions are also disclosed by Applicant as being specific for HLA-A *02 binding (See Table 8). Applicant has reduced to practice SEQ ID NO: 405 which encodes an inhibitory receptor specific to an HLA-A *03 allele (See Example 13 and Fig 26A). However SEQ ID NO: 405 does not share 80% sequence identity with SEQ ID NOs 305 and therefore is not encompassed by the instant claims.
The breadth of the claims encompass a genus of T cells responsive to loss of heterozygosity at an HLA-A *03 allele and a genus of polynucleotide systems comprising a genus of HER2 specific activating receptors comprising a polypeptide sequence having 80% identity to SEQ ID NO: 291 (or polynucleotide sequence having 80% identity to SEQ ID NO: 292) and a genus of HLA-A *03 inhibitory receptors comprising a polypeptide sequence having 80% identity to SEQ ID NO: 305 (or polynucleotide sequence having 80% identity to SEQ ID NO: 306). However, the present specification provides no guidance nor description of any rationale for determining which of the instantly claimed sequences encode an activating receptor specific to HER2 or an inhibitory receptor specific for an HLA-A *03 allele and, as such, a skilled artisan would not be able to determine which, if any, of the instantly disclosed SEQ ID NOs could be chosen in order to provide the claimed functional effect of HER2 and HLA-A *03 allele binding. Hence, based on the new written description guidelines, the Examiner should conclude that the applicant was not in possession of the claimed genus of T cells and polynucleotide sequences comprising an inhibitory receptor comprising the SEQ ID NOs as instantly claimed which are specific to HER2 and/or an HLA-A *03 allele.
Therefore, it is incumbent on the applicant to provide this nexus between structure and function, in order to be given credit for possession of a larger genus of nucleic acids related to those comprising these individual species. Otherwise, the Written Description guidelines suggest that the applicant is entitled to only the species specifically recited as having this activity. Moreover, even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the 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 to provide a "representative number” of species.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
The method of making the claimed invention is not well established. Although the screening of receptor binding of biological ligands is routine and conventional, one of skill in the art would neither expect nor predict the appropriate functioning of the HER2 specific activator and HLA-A *03 specific inhibitory receptors produced according to the broadly claimed genus of SEQ ID NOs as instantly claimed. It is well known that even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proceedings of the National Academy of Sciences USA, Vol., 79, Pg. 1979, 1982). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. While Applicant appears to account for this by claiming polypeptides comprising specific SEQ ID NOs which correspond to CDRs, framework mutations surrounding the CDRs can also have an effect. Panka et al. (Proceedings of the National Academy of Sciences USA, Vol., 85, 1988) teach that a single amino acid difference in a framework residue at the boundary with CDR3 was responsible for the decreased affinity of an anti-digoxin antibody (Pg. 3083, Column 1, 1st partial para.). Additionally, D’Angelo et al. (2018, Frontiers in immunology, 9, 395) reviews that it is well recognized in the art that third CDR of the heavy chain determines binding specificity and evidences that specific binding is not only dependent upon the CDR3 of the heavy chain, but also the surrounding heavy and light regions (Pg. 8, left col, 1st full para continued to right col.), which supports the assertion that not only would a sequence comprising a CHR-H3 specific for HLA-A*02 likely not bind to HLA-A*03, but also that the regions surrounding a particular CDR-H3 are also important for appropriate binding. Thus, it was well established in the art that the skilled artisan generally would not be able to visualize or otherwise predict, a priori, which, if any substitutions in the amino acid sequence of one or more of the CDRs would preserve the function of antigen binding for a particular antibody. Instead, trial-and-error experimentation was generally required to make and then select variants that retained antigen-binding activity.
Applicant has claimed a genus of T cells and polynucleotide systems comprising HER2 specific activator receptors and HLA-A *03 inhibitory receptors, yet the specification has only managed to identify very specific SEQ ID NOs which correspond to HER2 specific activator receptors and HLA-A *03 specific inhibitory receptors. Independent of how these specific sequences were arrived upon by Applicant, a HER2 specific activator receptor and/or an HLA-A *03 inhibitory receptor cannot have any position modified and predictably produce functional receptor having the appropriate specificity. Because Applicant has no manner a priori to predict which SEQ ID NO of HER2 specific activator receptors or HLA-A *03 specific inhibitory receptors can be modified while maintaining functionality, the genus of T cells and polynucleotides comprising the genus of HER2 specific activator receptors and HLA-A *03 specific inhibitory receptors as claimed by Applicant cannot be predictably made or used by the ordinary artisan.
Not knowing, absent further experimentation and screening, which modifications function and which do not, when, as set forth above, even a single change of an encoded amino acid can unpredictably affect structure and function, leads to one having no predictability or expectation of success for the function of any given modification to the activator receptor and inhibitory receptor SEQ ID NOs. Such random experimentation to identify, at a later time, what structure or variant or modification is or is not functional is embraced by Applicant’s claims and considered undue experimentation. Furthermore, functionally defined genus claims (i.e., a target specific activator or inhibitor receptor) can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. See ABBVIE DEUTSCHLAND GMBH & 2 CO. v. JANSSEN BIOTECH, INC., Appeals from the United States District Court for the District of Massachusetts in Nos. 09-CV-11340-FDS, 10-CV-40003-FDS, and 10-CV-40004-FDS, Judge F. Dennis Saylor, IV. See also Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein).
CONCLUSION
Therefore, the examiner concludes that there is insufficient written description of the instantly claimed genus of T cells responsive to loss of heterozygosity at an HLA-A *03 allele and polynucleotide systems. There is limited description of the structure-function relationship between the claimed genus of T cells and polypeptide systems comprising the instantly claimed polypeptide/polynucleotide sequences and their ability to produce HER2 specific and HLA-A *03 specific receptors. Specifically, the limited description of the structure-function relationship is related to the breadth of the permissible variability related to alterations of the disclosed SEQ ID NOs corresponding to HER2 specific activator receptors and HLA-A *03 specific inhibitory receptors as well as the claimed inhibitory receptor comprising a polypeptide sequence at least 80% identical to SEQ ID NO: 305 (and polynucleotide SEQ ID NO: 292) and comprising an scFv comprising SEQ ID NOs: 98, 90 or 91, 92, 95, 98, and 101 and its ability to function as a HLA-A *03 specific inhibitory receptor. Similarly, there is limited description of the structure-function relationship between the instantly claimed polypeptide sequences encoding the activator and inhibitory receptors (i.e., sequences 80% similar to SEQ ID NOs: 291 and 305 respectively) and their ability to function as HER2 activator receptors and HLA-A *03 inhibitory receptors in the claimed genus of polynucleotide systems.
Therefore, the Examiner further concludes a skilled artisan would find the specification inadequately describes the T cells responsive to loss of heterozygosity at an HLA-A *03 allele encompassed by the claimed genus of activating receptors having a polypeptide sequence at least 80% identical to SEQ ID NO: 291 comprising an scFv comprising SEQ ID NOs; 30, 32, 34, 36, 38, and 41 (and polynucleotide sequence at least 80% identical to SEQ ID NO: 292 encoding the claimed activator receptor) and the claimed genus of inhibitory receptors having a polypeptide sequence at least 80% identical to SEQ ID NO: 305 and comprising an scFv comprising SEQ ID NOs: 98, 90 or 91, 92, 95, 98, and 101 (and the polynucleotide sequence at least 80% identical to SEQ ID NO: 306 encoding the claimed inhibitory receptor). Similarly, the Examiner concludes a skilled artisan would find the specification inadequately describes the polynucleotide system encompassed by the claimed genus of SEQ ID NOs comprising the claimed HER2 specific activator receptor and HLA-A *03 specific inhibitory receptor.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIN V PAULUS whose telephone number is (571)272-6301. The examiner can normally be reached Mon-Fri 8 AM-5 PM.
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/ERIN V PAULUS/Examiner, Art Unit 1631
/ARTHUR S LEONARD/Examiner, Art Unit 1631