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 .
Claims 12-31 are pending and under examination.
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 12-14, 16 and 18-31 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for,
“A method for detecting a patient's immune response to an oligopeptide, the method comprising the steps of:
i. providing a mammalian cell comprising:
(a) a chimeric antigen-receptor polypeptide heterodimer comprising a first polypeptide and a second polypeptide, wherein:
(I) the first polypeptide comprises an extracellular part of a major histocompatibility complex I (MHC class I) alpha chain and the second polypeptide comprises a β2-microglobulin domain, or
(II) the first polypeptide comprises an extracellular part of a major histocompatibility complex II (MHC class II) alpha chain and the second polypeptide comprises an extracellular part of the major histocompatibility complex II (MHC class II) beta chain,
wherein at least one of the first and second polypeptides comprises the oligopeptide, and
wherein in (I) the extracellular part of the MHC class I alpha chain of the first polypeptide retains the ability to interact with the oligopeptide and with CD8, and
wherein in (II) the extracellular parts of the MHC alpha and beta chains retain the ability to interact with the oligopeptide and CD4, and
wherein one of the first polypeptide and the second polypeptide further comprises a hinge region, a transmembrane domain, and an intracellular domain or intracellular tail of a T cell receptor alpha chain, and the other of the first polypeptide and the second polypeptide comprises a hinge region, a transmembrane domain, and an intracellular domain of a T cell receptor beta chain; and
(b) a reporter gene functionally linked to the chimeric antigen-receptor polypeptide heterodimer,
ii. providing a blood sample of the patient ex-vivo,
iii. contacting the mammalian cell with the blood sample, and
iv. detecting said expression of the reporter protein gene in the mammalian cell,
does not reasonably provide enablement for the claimed “method for detecting a patient's immune response to an oligopeptide, the method comprising the steps of…” wherein the “chimeric antigen-receptor polypeptide heterodimer comprising a first polypeptide and a second polypeptide” of the instant claims is one wherein (I) the first polypeptide comprises any extracellular part of a MHCI alpha chain and the second polypeptide comprises a β2-microglobulin domain, or (II) the first polypeptide comprises any extracellular part of a MHCII alpha chain and the second polypeptide comprises any extracellular part of a MHCII beta chain, wherein at least one of the first and second polypeptides comprises the oligopeptide, and wherein one of the first polypeptide and the second polypeptide further comprises a hinge region, a transmembrane domain, and an intracellular domain or intracellular tail of a T cell receptor alpha chain, and the other of the first polypeptide and the second polypeptide comprises a hinge region, a transmembrane domain, and an intracellular domain of a T cell receptor beta chain; and (b) a reporter gene functionally linked to the chimeric antigen-receptor polypeptide heterodimer,
ii. providing a blood sample of the patient ex-vivo,
iii. contacting the mammalian cell with the blood sample, and
iv. detecting said expression of the reporter protein gene in the mammalian cell.
Polypeptides that comprise an extracellular domain / an extracellular part of the MHC class I alpha chain or the MHC class II alpha / beta chains given their broadest reasonable interpretation consistent with the teachings of the instant specification and the plain meaning these phases would have to the skilled artisan encompass in their breadth polypeptides comprising any one or more amino acids of the MHC class I polypeptide alpha chain or of the MHC class II alpha or beta chains.
However, 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 use chimeric antigen-receptor polypeptide heterodimers commensurate in scope with these claims.
The MHC class I derived chimeric antigen-receptor polypeptide taught by the instant specification is based upon the full-length α1, α2 and α3 domains present in naturally occurring MHC class I alpha chain, said alpha chain optionally modified to accommodate a peptide at the terminus of MHC class I.
Similarly, the MHC class II derived chimeric antigen-receptor polypeptide heterodimers specifically taught by the instant specification are based upon the full-length α1 and α2 / β1 and β2 domains present in naturally occurring MHC class II or optionally modified to accommodate a peptide at the N-terminus of said α1 and/or β1 domains.
The instant specification does not teach the skilled artisan how to practice “[a] method for detecting a patient's immune response to an oligopeptide antigenic peptide, the method comprising the steps of: i. providing mammalian cell comprising: (a) a chimeric antigen-receptor polypeptide heterodimer…” having the structural features recited in claim 12 parts (a)(I) or (a)(II), wherein (I) the first polypeptide comprises any extracellular part of a MHCI alpha chain and the second polypeptide comprises a β2-microglobulin domain, or (II) the first polypeptide comprises any extracellular part of a MHCII alpha chain and the second polypeptide comprises any extracellular part of a MHCII beta chain, wherein at least one of the first and second polypeptides comprises the oligopeptide, which encompasses in its breadth, e.g., MHC class I or class II polypeptides which lack, e.g., the CD8 and/or the CD4 binding domains of the MHC class I and/or MHC class II polypeptides (see Brogdon et al., J Immunol 1998; 161:5472-5480, at Introduction section on pages 5472-73, cited on an IDS).
The skilled artisan would not know how to use chimeric antigen-receptor polypeptide heterodimers lacking the CD8 and/or the CD4 binding portions of MHC class I and/or MHC class II. One reason for this is because TCRs lacking the ability to bind CD8 and/or CD4 exhibit altered signaling (see Brogdon at page 5472, left col.; see also Anel et al., Eur. J. Immunol. 1996.26: 2310-2319, at page 2310-11 bridging paragraph – 1st full paragraph on 2311, and Discussion, cited on and IDS) and undue experimentation would be required of the skilled artisan to calibrate intracellular signaling mediated by the transmembrane / intracellular domains of the TCR alpha and beta chains in the absence of normal CD8-MHC class I and/or CD4-MHC class II binding, if such is even at all possible.
Moreover, it further would have been unclear to the skilled artisan how to make and use chimeric antigen-receptor polypeptide heterodimers comprising any extracellular part of MHC class I and/or MHC class II when the specification provides the skilled artisan with insufficient guidance or direction as to how to modify the MHC class I or class II polypeptides while maintaining the structural elements necessary to mediate physiologically accurate TCR-MHC binding affinity / binding geometry in order to ensure any given oligopeptide identified by the claimed assay will continue to be capable of inducing physiologically accurate TCR signaling when presented in the context of endogenous MHC class I or class II in vivo (see Kuhns et al., Frontiers in Immunology, 2012, Vol. 3, Article 159, pages 1-13, cited on an IDS, “Macromolecular Complexes and Geometric Constraints on TCR Signaling” at pages 5-7 and Fig. 2).
Notably, given the binding interactions between certain portions of the extracellular domains of the TCR and the CD3 chains are likewise crucial for TCR:CD3-mediated signal transduction, the skilled artisan would be further uncertain about their ability to modify the structure of the MHC class II extracellular domain without adversely affecting the chimeric antigen-receptor’s signaling ability.
In conclusion, the instant claims encompass an invention of tremendous breadth, and essentially call for undue trial and error experimentation by the skilled artisan to begin discovering how to make and use the claimed invention without assisting the skilled artisan in such an endeavor, which is insufficient to constitute adequate enablement.
The scope of the claims must bear a reasonable correlation with the scope of enablement. In re Fisher, 166 USPQ 18(CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute.
Undue experimentation would be required to produce the invention commensurate with the breadth of the claims based on the disclosure of the instant specification and the knowledge in the art. Reasonable correlation must exist between the scope of the claims and scope of enablement set forth. 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 claimed invention.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 12-31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 11939572 (cited on an IDS) in view of McGinty et al. (Diabetes Volume 63, September 2014, pp 3033-3040 and Supp pages 1-6) (cited herewith).
Reference claims 1-10 are drawn to methods for the identification of a TCR recognizable peptide sequence comprising a first step (“step i") that is substantially similar to the claimed method but for the reference methods being designed to identifying “a TCR recognizable peptide sequence” rather than “detecting a patient’s immune response to an oligopeptide.”
For example, reference claim 1 reads as follows:
PNG
media_image1.png
740
405
media_image1.png
Greyscale
PNG
media_image2.png
320
388
media_image2.png
Greyscale
However, the reference claims are not drawn to a method for detecting a patient's immune response to an oligopeptide, the method comprising the steps of:
i. providing a mammalian cell comprising:
(a) a chimeric antigen-receptor polypeptide heterodimer comprising a first polypeptide and a second polypeptide, wherein:
(I) the first polypeptide comprises an extracellular part of a major histocompatibility complex I (MHC class I) alpha chain and the second polypeptide comprises a β2-microglobulin domain, or
(II) the first polypeptide comprises an extracellular part of a major histocompatibility complex II (MHC class II) alpha chain and the second polypeptide comprises an extracellular part of the major histocompatibility complex II (MHC class II) beta chain,
wherein at least one of the first and second polypeptides comprises the oligopeptide, and
wherein one of the first polypeptide and the second polypeptide further comprises a hinge region, a transmembrane domain, and an intracellular domain or intracellular tail of a T cell receptor alpha chain, and the other of the first polypeptide and the second polypeptide comprises a hinge region, a transmembrane domain, and an intracellular domain of a T cell receptor beta chain; and
(b) a reporter gene functionally linked to the chimeric antigen-receptor polypeptide heterodimer,
ii. providing a blood sample of the patient ex-vivo,
iii. contacting the mammalian cell with the blood sample, and
iv. detecting said expression of the reporter protein gene in the mammalian cell.
McGinty teaches that a small fraction of CD4 T cells that recognize modified GAD65 epitopes can be detected in peripheral blood samples from subjects with type I diabetes, but said CD4 T cells can only be detected with an enrichment strategy based on anti-phycoerythrin (anti-PE) magnetic beads (see page 3034-35 bridging paragraph; page 3036, 1st full paragraph; Supplemental Figure 2).
At the second paragraph of the Discussion section, McGinty further teaches (emphasis added):
“CD4+ T cells that recognize modified epitopes were not present at elevated frequencies in islet autoantibody–positive nondiabetic individuals, indicating that accumulation of these T cells is not directly linked to autoantibody development; rather these cells may be associated with a later stage of progression. Notably, subjects with type 1 diabetes had higher frequencies of memory (CD45RO+) cells specific for GAD65-modified epitopes than healthy controls. Subjects with type 1 diabetes also had higher frequencies of naïve (CD45RO−) cells specific for GAD65-modified epitopes, suggesting that subjects who progress to develop diabetes may select a larger repertoire of potentially autoreactive T cells that recognize these modified GAD65 epitopes. Alternatively, these could be antigen experienced CD4+ T cells that have lost CD45RO expression due to chronic antigen exposure. The mere presence of CD4+ T cells that recognize modified GAD65 epitopes does not guarantee that these cells play a role in diabetes. However, T-cell clones that recognize modified epitopes predominantly secreted TNF-α and interferon-γ. This Th1-like phenotype supports the relevance of T-cell recognition of modified antigens in the loss of tolerance in type 1 diabetes.”
Given the teachings of the reference claims in view of McGinty it would have been obvious to one of ordinary skill in the art to convert the method for the identification of a TCR recognizable peptide sequence to a method for detecting a patient’s peripheral blood immune response to an oligopeptide associated with type I diabetes pathogenesis, such as the citrullinated GAD65 peptide sequences described by McGinty (see, e.g., Table 1), especially in those patients at risk of type I diabetes, or at risk for exacerbation thereof, wherein increased frequency of citrullinated GAD65 peptide reactive T-cells is suggested by the teachings of McGinty to suggestive of increased disease risk.
Note that as set forth in MPEP § 1481.03(II)(A), “…there is significance to the designation of the relationship as "continuation," "divisional," or "continuation-in-part." For example, the safe harbor of 35 U.S.C. 121 only protects divisional applications, not continuation applications or continuation-in-part applications. See Pfizer, Inc. v. Teva Pharmaceuticals USA, Inc., 518 F.3d 1353, 1362, 86 USPQ2d 1001, 1007-08 (Fed. Cir. 2008) and Amgen v. Hoffman-La Roche, 580 F.3d 1340, 1352-1354, 92 USPQ2d 1289, 1298-1300 (Fed. Cir. 2009). Changing the relationship to or from a "divisional" has the potential to impact the applicability of the safe harbor provision or a nonstatutory double patenting rejection.” (emphasis added).
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY S SKELDING whose telephone number is (571)272-9033. The examiner can normally be reached M-F 9-5 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644
Prosecution Insights