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 .
DETAILED ACTION
Application status
In response to the previous Office action, a non-Final rejection (mailed on 10/20/2025), Applicants filed a response and amendment received on 02/19/2026. Said amendment canceled Claims 23-41, amended Claims 1, 3, 5, 9-22, and added Claims 42-63. Thus, Claims 1-5, 9-22 and 42-63 are at issue and present for examination.
Claim Rejections - 35 U.S.C. § 112 - WITHDRAWN
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 previous rejection of Claims 3, 5 and 9-40 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn by virtue of Applicants’ amendment.
Claim Rejections - 35 U.S.C. § 112 – A New Rejection necessitated by Applicants’ amendment
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.
Claims 1-5, 10-21 and 42-63 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 (2-5, 10-21 and 42-63 dependent therefrom) recite “wherein the CD2 extracellular domain comprises a D111H mutation” which is unclear and indefinite. It is unclear where this mutation is located, especially because it is ambiguous to determine which exact amino acid residues are included within the CD2 extracellular domain. For example, one person may deem said domain spans 75-982 aa residues while another person may deem said domain spans 86-985, making the mutation position unclear. Furthermore, the phrase “CD2 extracellular domain” is not defined in the specification. The Examiner suggests inserting a SEQ ID NO corresponding to the CD2 extracellular domain, i.e., ---wherein the CD2 extracellular domain comprises the amino acid sequence as set forth in SEQ ID NO: 3 with a D111H mutation---. It is noted by the Examiner that none of the dependent claims remedy the deficiency noted above except for claims 9 and 22. In the interest of advancing prosecution, the noted phrase is interpreted as “wherein the CD2 extracellular domain comprises a mutation”.
Claim Rejections - 35 U.S.C. § 112(a) Written Description – WITHDRAWN
The following is a quotation 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 previous rejection of Claims 1-21 under 35 U.S.C. § 112(a), written description, 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(s), at the time the application was filed, had possession of the claimed invention, is withdrawn by virtue of Applicants’ amendment.
Claim Rejections - 35 U.S.C. § 112(a) Enablement – MAINTAINED as necessitated by Applicants’ amendment
Claims 1-5 and 9-21 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for a non-naturally occurring chimeric stimulatory receptor (CSR) comprising: (a) an ectodomain comprising a signal peptide and an activation component, wherein the signal peptide comprises a CD2 signal peptide or a CD8α signal peptide, and wherein the activation component comprises a CD2 extracellular domain to which an agonist binds; (b) a transmembrane domain, wherein the transmembrane domain comprises a CD2 transmembrane domain; and (c) an endodomain comprising a cytoplasmic domain and a signal transduction domain, wherein the cytoplasmic domain is a CD2 intracellular domain, a CD28 intracellular domain, a 4-1BB intracellular domain, an IL17RA intracellular domain, an IL15RA intracellular domain, an IL21R intracellular domain, an ICOS intracellular domain, a CD27 intracellular domain, an OX40 intracellular domain or a GITR intracellular domain, and wherein the signal transduction domain comprises a CD3ζ protein; and
wherein the CSR comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 47, SEQ ID NO: 51, SEQ ID NO: 55, SEQ ID NO: 59, SEQ ID NO: 63, SEQ ID NO: 67, SEQ ID NO: 71, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61, SEQ ID NO: 65, SEQ ID NO: 69 or SEQ ID NO: 73, does not reasonably provide enablement for any non-naturally occurring chimeric stimulatory receptor (CSR) comprising: (a) an ectodomain comprising a signal peptide and an activation component, wherein the signal peptide comprises any CD2 signal peptide or any CD8a signal peptide, and wherein the activation component comprises any CD2 extracellular domain to which an agonist binds; (b) any transmembrane domain, wherein the transmembrane domain comprises any CD2 transmembrane domain, and (c) an endodomain comprising any cytoplasmic domain and any signal transduction domain, wherein the cytoplasmic domain is any CD2 intracellular domain, any CD28 intracellular domain, any 4-1BB intracellular domain, any IL17RA intracellular domain, any IL15RA intracellular domain, any IL21R intracellular domain, any ICOS intracellular domain, any CD27 intracellular domain, any OX40 intracellular domain or any GITR intracellular domain, and wherein the signal transduction domain comprises any CD3ζ intracellular domain; and wherein the signal peptide and the cytoplasmic domain are not derived from the same protein; and wherein the CD2 extracellular domain comprises any mutation. (see above 112(b) rejection for the claim interpretation)
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2nd 1400 (Fed. Cir. 1988)) as follows: 1) quantity of experimentation necessary, 2) the amount of direction or guidance presented, 3) the presence and absence of working examples, 4) the nature of the invention, 5) the state of prior art, 6) the relative skill of those in the art, 7) the predictability or unpredictability of the art, and 8) the breath of the claims. The factors which have lead the Examiner to conclude that the specification fails to teach how to make and/or use the claimed invention without undue experimentation, are addressed in detail below.
The breath of the claims. Claims are so broad as to encompass any non-naturally occurring chimeric stimulatory receptor (CSR) comprising: (a) any ectodomain comprising any signal peptide and any activation component, wherein the signal peptide comprises any CD2 signal peptide or any CD8a signal peptide, and wherein the activation component comprises any CD2 extracellular domain to which an agonist binds; (b) any transmembrane domain, wherein the transmembrane domain comprises any CD2 transmembrane domain, and (c) any endodomain comprising any cytoplasmic domain and any signal transduction domain, wherein the cytoplasmic domain is any CD2 intracellular domain, any CD28 intracellular domain, any 4-1BB intracellular domain, any IL17RA intracellular domain, any IL15RA intracellular domain, any IL21R intracellular domain, any ICOS intracellular domain, any CD27 intracellular domain, any OX40 intracellular domain or any GITR intracellular domain, and wherein the signal transduction domain comprises any CD3ζ intracellular domain; and wherein the signal peptide and the cytoplasmic domain are not derived from the same protein; and wherein the CD2 extracellular domain comprises any mutation. The enablement provided is not commensurate in scope with the claim due to the extremely large number of protein domains of unknown structure that be used in making the CSRs as encompassed by the claims. It is noted by the Examiner that the instant specification does not define the phrase reciting each ‘domain’ with a specific amino acid sequence. Therefore, the noted phrase can be broadly and reasonably interpreted to encompass any length of amino acids containing the recited domains from any orthologs having the same name. In the instant case, the specification enables for a non-naturally occurring chimeric stimulatory receptor (CSR) comprising: (a) an ectodomain comprising a signal peptide and an activation component, wherein the signal peptide comprises a CD2 signal peptide or a CD8α signal peptide, and wherein the activation component comprises a CD2 extracellular domain to which an agonist binds; (b) a transmembrane domain, wherein the transmembrane domain comprises a CD2 transmembrane domain; and (c) an endodomain comprising a cytoplasmic domain and a signal transduction domain, wherein the cytoplasmic domain is a CD2 intracellular domain, a CD28 intracellular domain, a 4-1BB intracellular domain, an IL17RA intracellular domain, an IL15RA intracellular domain, an IL21R intracellular domain, an ICOS intracellular domain, a CD27 intracellular domain, an OX40 intracellular domain or a GITR intracellular domain, and wherein the signal transduction domain comprises a CD3ζ protein; and wherein the CSR comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 47, SEQ ID NO: 51, SEQ ID NO: 55, SEQ ID NO: 59, SEQ ID NO: 63, SEQ ID NO: 67, SEQ ID NO: 71, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61, SEQ ID NO: 65, SEQ ID NO: 69 or SEQ ID NO: 73.
The amount of direction or guidance presented and the existence of working examples. The specification discloses the amino acid sequences of CSRs as set forth in SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 47, SEQ ID NO: 51, SEQ ID NO: 55, SEQ ID NO: 59, SEQ ID NO: 63, SEQ ID NO: 67, SEQ ID NO: 71, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61, SEQ ID NO: 65, SEQ ID NO: 69 or SEQ ID NO: 73 (see para [013]and [014]). However, the specification fails to provide any clue as to the structural elements required in any CSRs comprising any of the recited domains with varying boundaries of said domains, in addition to including any orthologs having the same domain names. The Examiner notes that the instant claims do not recite that the claimed CSR is a human CSR.
Moreover, the specification fails to provide any clue as to the structure elements required in any CSR comprising the recited endodomain which comprises any one of any CD2 intracellular domain, any CD28 intracellular domain, any 4-1BB intracellular domain, any IL17RA intracellular domain, any IL15RA intracellular domain, any IL21R intracellular domain, any ICOS intracellular domain, any CD27 intracellular domain, any OX40 intracellular domain and any GITR intracellular domain. Taken together, the specification is silent with regard to which of these extremely large number of diverse structures of CSRs made up of the recited domains are essential for a desired activity of the claimed CSRs. No correlation between structure and function has been presented. There is no information or guidance as to which of the recited domains can be used in order to obtain a desired activity of claimed CSRs.
The state of prior art, the relative skill of those in the art, and the predictability or unpredictability of the art. While the art discloses several chimeric receptors, neither the specification nor the art provide a correlation between structure and a desired activity of any CSRs such that one of skill in the art can envision extremely wide number of structures of any CSRs comprising any recited (encompassing any length of amino acids from any of the recited domains including orthologous domains), optionally wherein the recited endodomain comprises any one of any CD2 intracellular domain, any CD28 intracellular domain, any 4-1BB intracellular domain, any IL17RA intracellular domain, any IL15RA intracellular domain, any IL21R intracellular domain, any ICOS intracellular domain, any CD27 intracellular domain, any OX40 intracellular domain or any GITR intracellular domain.
The quantity of experimentation required to practice the claimed invention based on the teachings of the specification. While methods of generating or making specific chimeric receptors were known in the art at the time of the invention, it was not routine in the art to screen by a trial and error process for all of the possible CSRs using any of the recited receptor domains for a desired activity. In the absence of (1) a rational and predictable scheme for modifying any and all of the recited CSR domains such that the resulting CSR would have the desired activity, and/or (2) a correlation between all of the encompassed structures of CSR domains and a desired activity, one of skill in the art would have to test an essentially extremely large number of recited CSR domains with varying length of amino acid sequences, in order to determine which ones have the desired activity.
It is noted by the Examiner that all of the dependent claims 2-5 and 9-21 are included in this rejection because none of them remedy the deficiencies found under the instant ‘scope of enablement’ rejection as discussed above.
Therefore, taking into consideration the extremely broad scope of the claim, the lack of guidance, the amount of information provided, the lack of knowledge about a correlation between structure and the desired function, and the high degree of unpredictability of the prior art in regard to structural changes in receptor domains and their effect on function, one of ordinary skill in the art would have to go through the burden of undue experimentation in order to practice the claimed invention. Thus, Applicant has not provided sufficient guidance to enable one of ordinary skill in the art to make and use the invention in a manner reasonably correlated with the scope of the claims.
Applicants’ Arguments:
Applicants argue that the amended claim 1 no longer recites "a portion thereof' with regard to the various domains of the CSRs and no longer recites combinations of cytoplasmic domains. For at least these reasons, substitute claim 1 and the claims dependent therefrom (substitute claims 2-5 and 9-21) do not lack enablement.
Examiner’s Explanation:
Applicants’ arguments have been fully considered but are not deemed persuasive for the following reasons. As explained above, just by deleting “a portion thereof” and “a combination thereof” in claim 1, does not enable one of skill art to make and use the invention as claimed in a manner reasonably correlated with the scope of the claims (see above explanation in the body of the instant rejection).
Conclusion
Claims 1-5, 9-21 and 42-63 are rejected/objected to for the reasons as stated above. It is noted by the Examiner that claim 22 would be allowable if written as an independent claim.
Applicants must respond to the objections/rejections in this Office action to be fully responsive in prosecution.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAE W LEE whose telephone number is (571)272-9949. The examiner can normally be reached on M-F between 9:00-6:00.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached on (571)272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JAE W LEE/
Examiner, Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656
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