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 44-63 are pending and under examination.
As noted in the attached interview summary, as a phone call was made to applicant’s representative Christine Lekutis 7-2-26 to inform her that if applicant were willing to file a terminal disclaimer directed to the patent that issued from the parent case, U.S. Patent No. 11753457, then the instant claims would be allowable. In a return phone call Mrs. Leuktis informed the undersigned that applicant was not willing to a file a pre-emptive terminal disclaimer.
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 44-46 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 24 of U.S. Patent No. 11753457, cited on an IDS, in view of Martinez-Llordella et al. (WO2020044055, cited herewith, hereinafter “Marc”), “Infusion of CAR T cells,” hereinafter “Infusion,” published 2-2021 by the attcnetwork.co.uk, pages 1-9, cited herewith; OpenTextBC, “Chapter 8. Intravenous Therapy,” pages 1-15 (2015), cited herewith, hereinafter “BC”; Donald Fleming, Protocols for concomitant infusions in the same IV line, 3-17-14, pages 1-2, cited herewith, hereinafter “Fleming”; as evidenced by Reich-Slotky et al., Volume 58, February 2018 Transfusion 339-344, cited herewith; and Iyer et al. (Front Med (Lausanne). 2018 May 23;5:150, cited herewith).
Reference claim 24 is drawn to a pharmaceutical composition comprising a plurality T cells modified to express a CAR comprising an antigen-binding domain, a hinge domain, a transmembrane domain, one or more co-stimulatory domains, and an intracellular signaling domain, wherein the antigen binding domain specifically binds to three or more different citrullinated proteins or citrullinated fragments thereof, and comprises complementarity-determining regions (CDRs) from VH and VL domains of SEQ ID NO:1 and SEQ ID NO:4,
wherein said plurality of T cells are (i) Treg T cells, (ii) human T cells, (iii) primary T-cells, and (iv) CD4+, CD25+ and CD127lo the T cells, and a pharmaceutically acceptable carrier.
However, the reference claim is not drawn to the kit of claims 44-46 comprising a container containing the pharmaceutical composition of reference claim 24, wherein said pharmaceutical composition communicating through a fluidic conduit with a drip chamber, wherein the drip chamber communicates through a fluidic conduit with an intravenous needle (claim 44), or wherein the container comprises a bag (claim 45), or wherein the fluidic conduit between the container and the needle comprises one or more Y-sites and a roller clamp (claim 46).
At page 2, last paragraph, Marc teaches:
“Thus, in a first aspect the present invention provides an engineered Treg comprising a chimeric antigen receptor (CAR) for use in induction of tolerance to a transplant; treating and/or preventing graft-versus-host disease (GvHD), an autoimmune or allergic disease; to promote tissue repair and/or tissue regeneration; or to ameliorate chronic inflammation secondary to metabolic disorders; wherein the CAR comprises an endodomain which comprises a STAT5 association motif and a JAKl- and/or a JAK2-binding motif.”
For example, in Fig. 2 Marc teaches various CARs that can be used to engineer Tregs for use in induction of tolerance to a transplant, and in Fig. 3A Marc teaches a scheme for Treg cell engineering and expansion based on (i) stimulation with anti-CD3/CD28 coated beads, (ii) transduction with lentiviral particles, and (iii) engineered Treg expansion.
Moreover, at page 7, 3rd full paragraph, Marc teaches modification of Tregs to express a foreign nucleic acid such as a polynucleotide encoding a CAR can occur via a variety of additional methods beyond viral vector transduction, such as transfection, electroporation and calcium phosphate.
With respect to administering said CAR containing Treg cells to a patient, at page 42-43 bridging para, Marc teaches:
“The Treg or pharmaceutical composition as described herein can be administered parenterally, for example, intravenously, or they may be administered by infusion techniques. The Treg or pharmaceutical composition may be administered in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solution may be suitably buffered (preferably to a pH of from 3 to 9). The pharmaceutical composition may be formulated accordingly. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.”
With respect to the particular device(s) used for i.v. administration of CAR T-cells, “Infusion” teaches a multi-step process comprising steps 3.5 and 3.6:
“Give IV Chlorphenamine and antiemetic as appropriate” and
“Spike 100ml N Saline bag with infusion IV giving set,”
to be followed by steps 4.3 and 4.7:
“Stop N Saline infusion, disconnect and insert spike of giving set into CAR T cell bag port” and “Once all requested bags infused attach 500 ml IV N Saline to clear line or for Autolus product, refer to appendix…Continue IV infusion with N Saline until line is as clear as possible.”
“Infusion” does not explicitly refer to the use of a pump to push the administered CAR T-cells through the infusion system; furthermore, despite some variability in administrations speeds, prior to applicant’s date of invention gravity-based infusion was routinely practiced for administration of hematopoietic cells, “[t]he rationale for this practice is not well established, and the general assumption has been that the peristalsis from the pump might damage the HPCs….” (see Reich-Slotky at page 339-40 bridging paragraph). Thus, given the knowledge in the prior art it would have been obvious to the ordinarily skilled artisan to administer CAR comprising T-cells via a gravity-based infusion system.
As to performing the steps of “Infusion” under the pressure of gravity, a typical “primary” and “secondary” IV infusion set up is described at pages 3-5 of BC. As shown in Fig. 8.4 of BC, a common set up comprising Primary and Secondary IV bags joined through “sterile spikes” to “drip chambers,” wherein the primary and secondar tubing lines meeting at a Y-shaped port that is in turn joined to at a “Roller clamp” for controlling IV infusion rates under Gravity -> drops/min, wherein the IV cannula provides the interface with the patient:
PNG
media_image1.png
734
550
media_image1.png
Greyscale
Note that the port which joins the Primary and Secondary IV lines is also referred to as a “Y-port” as described by Fleming could have a variety of uses, “…such as administering chemotherapeutic agents concurrently with supportive care fluids and/or medications.” (see page 1, 2nd paragraph).
Given the reference teachings it would have been obvious to one of ordinary skill in the art to prepare a kit comprising a pharmaceutical composition comprising a plurality of T cells modified to express a CAR comprising an antigen-binding domain of reference claim 24, and further comprising the components that facilitate intravenous infusion of such T cells, including infusion tubing, drip chambers, one or more Y-sites and roller clamps, and needles for intravenous administration. The ordinarily skilled artisan would have been motivated to bundle said components in a kit format to facilitate convenient shipping, e.g., from a CAR T-cell production site to the point of care given that centralized manufacturing of CAR T-cell products offers numerous advantages (see, e.g., Iyer at page 2, 2nd and 3rd paragraphs of the left col. and Fig. 1).
In view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claims 47-49, 54-56 and 59 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 25-30 of U.S. Patent No. 11753457, cited on an IDS.
Reference claim 25 is drawn to “a method of treating a human subject suffering from rheumatoid arthritis, comprising administering to the subject an effective amount of [a] pharmaceutical composition comprising a plurality of the modified T cells, wherein the T cell is CD4+, CD25+ and CD127lo, wherein the T cell is a primary T-cell, wherein the T cell is a human T cell, wherein the T cell is a Treg cell, wherein the T-cell expresses a chimeric antigen receptor (CAR) comprising an antigen-binding domain, a hinge domain, a transmembrane domain, one or more co-stimulatory domains, and an intracellular signaling domain, wherein the antigen binding domain specifically binds to three or more different citrullinated proteins or citrullinated fragments thereof, and comprises complementarity-determining regions (CDRs) from VH and VL domains of SEQ ID NO:1 and SEQ ID NO:4.”
Reference claim 28 is drawn to “[a] method of treating a human subject suffering from rheumatoid arthritis, the method comprising: (a) isolating T cells from a biological sample obtained from the subject; (b) enriching the T cells for T regulatory cells (Treg); (c) transfecting the enriched Treg cells with an expression vector encoding a chimeric antigen receptor (CAR) comprising an antigen-binding domain, a hinge domain, a transmembrane domain, one or more co-stimulatory domains, and an intracellular signaling domain, wherein the antigen binding domain specifically binds to three or more different citrullinated proteins or citrullinated fragments thereof, and comprises complementarity-determining regions (CDRs) from VH and VL domains of SEQ ID NO:1 and SEQ ID NO:4; (d) expanding the transfected Treg cells; and (e) administering the expanded Treg cells to the subject.”
Reference claims 29 and 30 are dependent on reference claim 28 and further specify that the exampansion does or does not comprise using anti-CD3/CD28 coated beads.
Rejected claims 47-49 and 54 are drawn to methods of preparing T regulatory cells consistent with steps (a) – (d) of reference claims 28, and as further modified by reference claims 29 and 30. In practicing the methods of treatment of reference claims 28-30 the ordinarily skilled artisan will necessarily be practicing rejected claims 47-49 and 54. Moreover, in practicing the method of treating of reference claim 28, the ordinarily skilled artisan will necessarily be producing the pharmaceutical compostion of instant claim 55 for “administering the expanded Treg cells to the subject” as recited in step (e) of reference claim 28.
Finally, reference claims 28-30 anticipate the method of treatment of instant claim 59.
Claim(s) 50 and 51 are rejected under 35 U.S.C. 103 as being unpatentable over claims 28-30 of U.S. Patent No. 11753457 as applied to claims 47-49 above, and further in view of Marc et al. (WO2020044055).
Reference claim 28 is drawn to “[a] method of treating a human subject suffering from rheumatoid arthritis, the method comprising: (a) isolating T cells from a biological sample obtained from the subject; (b) enriching the T cells for T regulatory cells (Treg); (c) transfecting the enriched Treg cells with an expression vector encoding a chimeric antigen receptor (CAR) comprising an antigen-binding domain, a hinge domain, a transmembrane domain, one or more co-stimulatory domains, and an intracellular signaling domain, wherein the antigen binding domain specifically binds to three or more different citrullinated proteins or citrullinated fragments thereof, and comprises complementarity-determining regions (CDRs) from VH and VL domains of SEQ ID NO:1 and SEQ ID NO:4; (d) expanding the transfected Treg cells; and (e) administering the expanded Treg cells to the subject.”
However, the reference claim does not explicitly teach the embodiments of dependent claims 50 and 51.
At page 2, last paragraph, Marc teaches:
“Thus, in a first aspect the present invention provides an engineered Treg comprising a chimeric antigen receptor (CAR) for use in induction of tolerance to a transplant; treating and/or preventing graft-versus-host disease (GvHD), an autoimmune or allergic disease; to promote tissue repair and/or tissue regeneration; or to ameliorate chronic inflammation secondary to metabolic disorders; wherein the CAR comprises an endodomain which comprises a STATS association motif and a JAKl- and/or a JAK2-binding motif.”
For example, in Fig. 2 Marc teaches various CARs that can be used to engineer Tregs for use in induction of tolerance to a transplant, and in Fig. 3A Marc teaches a scheme for Treg cell engineering and expansion based on (i) stimulation with anti-CD3/CD28 coated beads, (ii) transduction with lentiviral particles, and (iii) engineered Treg expansion.
Moreover, at page 7, 3rd full paragraph, Marc teaches modification of Tregs to express a foreign nucleic acid such as a polynucleotide encoding a CAR can occur via a variety of additional methods beyond viral vector transduction, such as transfection, electroporation and calcium phosphate.
With respect to administering said CAR containing Treg cells to a patient, at page 42-43 bridging para, Marc teaches:
“The Treg or pharmaceutical composition as described herein can be administered parenterally, for example, intravenously, or they may be administered by infusion techniques. The Treg or pharmaceutical composition may be administered in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solution may be suitably buffered (preferably to a pH of from 3 to 9). The pharmaceutical composition may be formulated accordingly. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.”
Given the teachings of Marc, in the course of practicing reference claim 28 it would have been obvious to one of ordinary skill in the art practicing step (c) (“transfecting the enriched Treg cells with an expression vector encoding the CAR of claim 1”) that said “transfecting” could be performed with viral vector encoding the CAR of interest, i.e., could be performed via transduction / transfection with, e.g., a lentiviral vector, or via any number of other methods as set forth by Marc. One reason the ordinarily skilled artisan would have been motivated to use lentiviral vector transduction / transfection to engineer Treg cells as set forth in the reference claims was because such techniques were long understood in the art to provide convenient delivery of nucleic acids to lymphocytes.
In view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claim(s) 52, 53, 60 and 61 are rejected under 35 U.S.C. 103 as being unpatentable over claims 25-30 of U.S. Patent No. 11753457 as applied to claims 47-49, 54-56 and 59 above, and further in view of Marc et al. (WO2020044055).
Claims 25-30 of U.S. Patent No. 11753457 as applied to claims 47-49, 54-56 and 59 are set forth above.
However, the reference claims do not explicitly recite the scFv limitation of instant claims 52, 53, 60 and 61.
At page 27, 2nd full paragraph, Marc teaches the preferred binding domain for a CAR is an scFv, and all of the CARs used to engineer Treg cells featured in Marc are CARs based on an scFv format (see, e.g., at Figs. 1-2 and SEQ ID NOs: 73-86 at pages 34-36).
Given the teachings of Marc, and further given the common knowledge of one of ordinary skill in the art that the use of an scFv format in the context of a CAR facilitates convenient expression from a single open reading frame, it would have been obvious to one of ordinary skill in the art, and one of ordinary skill in the art would have been motivated to use, e.g., the VH and VL domains of SEQ ID NOs: 1 and 4 of reference claim 11 in the context of an scFv format as set forth in SEQ ID NO: 5 of reference claim 14 for a process of making a chimeric antigen receptor (CAR) comprising an antigen-binding domain, a hinge domain, a transmembrane domain, one or more co-stimulatory domains, and an intracellular signaling domain, wherein the antigen binding domain specifically binds to three or more different citrullinated proteins or citrullinated fragments thereof, and comprises complementarity-determining regions (CDRs) from VH and VL domains of SEQ ID NO:1 and SEQ ID NO:4.
Thus, the methods of making / methods of treating of instant claims 52, 53, 60 and 61 were obvious in view of the reference claims and the teachings of Marc.
In view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claim(s) 57, 58, 62 and 63 are rejected under 35 U.S.C. 103 as being unpatentable over claims 25-30 of U.S. Patent No. 11753457 as applied to claims 47-49, 54-56 and 59 above, and further in view of Nguyen et al. (J Exp Med 27 June 2016; 213 (7): 1241–1253, cited herewith).
A description of reference claims 25-30 of U.S. Patent No. 11753457 as applied to claims 47-49, 54-56 and 59 is set forth above.
However, these reference claims do not further include methods of treating rheumatoid arthritis by administering both the CAR expressing Treg cells and an anti-inflammatory agent such as anti-TNF antibody.
Nguyen teaches the binding of anti-TNF antibody adalimumab paradoxically promoted the interaction between monocytes and T reg cells isolated from patients with rheumatoid arthritis (RA), and that this promotes Treg cell expansion (see Abstract). At page 1241, last full paragraph Nguyen describes that “Anti-TNF therapy has revolutionized the therapy of a
variety of inflammatory diseases including RA.”
Given the reference claims and the teachings of Nguyen it would have been obvious to one of ordinary skill in the art, and one of ordinary skill in the art would have been motivated to administer the CAR Treg cells of the reference claims in conjunction with anti-TNF antibody for the treatment of rheumatoid arthritis.
In view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
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