DETAILED ACTION
Status of Application, Amendments and/or Claims
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The amendment of 5/29/26 has been entered in full. Claims 1-2, 6-13 and 17-20 are amended. Claims 1-20 are pending.
Applicants’ election of Group I, claims 1-11, was previously acknowledged and treated as an election without traverse. Claims 12-20 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
The following elections of species were also previously acknowledged:
(1) CD22 as the species of first antigen;
(2) T-cell as the species of immune cell;
(3) cytokine secretion as the species of cellular activity; and
(4) cell culture plate as the species of support;
Claim 5 remains withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1-4 and 6-11 are under consideration.
Withdrawn Objections and/or Rejections
The following page numbers refer to the previous Office Action (3/24/26).
The objections to claims 10 and 11 at page 3 are withdrawn in view of the amendments to the claims.
The rejection of claims 1-4 and 6-11 at page 3 under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter is withdrawn in view of the amendments to the claims.
Maintained Objections and/or Rejections
Note on Prior Art Rejection(s)
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
Claims 1-4 and 6-11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bedoya et al, U.S. Patent Application Publication 2017137783, published 5/18/17 (cited on the 12/16/22 IDS). The earliest date to which the instant application claims priority is 7/3/20. This rejection was set forth at pages 4-6 of the 3/24/26 Office Action.
The rejection is first restated in view of the amendments to the claims, and then Applicants’ arguments are addressed.
Applicants have amended independent claim 1 in three substantive ways: (1) the intended use of the preamble has been changed from “of characterizing the potency of an immune cell expressing a chimeric antigen receptor (CAR)” to “for validating a pharmaceutical grade product that comprises activated and expanded immune cells expressing a [CAR] targeting an antigen”; (2) the “comprising” transitional phrase that introduces the method steps has been amended to “comprising characterizing the potency of said immune cells by”; and (3) in the product of the first method step has been changed from an “immune cell” to “a sample of the cell product comprising activated and expanded immune cells”.
As such, claim 1 as amended now encompasses an in vitro method for validating a pharmaceutical grade product that comprises activated and expanded immune cells expressing a chimeric antigen receptor (CAR) targeting an antigen, where said method comprises characterizing the potency of said immune cells via three method steps: (i) providing a sample of the cell product comprising activated and expanded immune cells expressing a CAR targeting an antigen, (ii) stimulating said immune cells by incubating said cells on a ligand-coated support, wherein said support is not a cell or bead, wherein the ligand comprises the target antigen, and (iii) determining the level of activity of the stimulated immune cells.
While the recitation in the amended preamble directs the in vitro method to use of “a pharmaceutical grade product that comprises activated and expanded immune cells expressing a [CAR] targeting an antigen”, this “cell product” is also required by the first method step, so the only further limitation provided by this phrase in the preamble is that the method is “for validating”. This recitation has been considered in the context of the entire claim and is interpreted as an intended use for the method because it does not result in a manipulative difference between the method as defined by the steps and a prior art method teaching the same steps. See MPEP 2111.02. As such, this intended use does not distinguish the claimed method from a prior art method comprising the same step(s). Furthermore, the new limitation that the method comprises “characterizing the potency of said immune cells” is met by practicing the third step of the method, “determining the level of activity of the stimulated immune cells”, so this recitation does not add any limitation beyond what is recited by the method steps.
As such, amended claim 1 encompasses any prior art method teaching an in vitro method comprising (i) providing a sample of a pharmaceutical grade cell product comprising activated and expanded immune cells expressing a CAR targeting an antigen; (ii) stimulating said cells by incubating the cells on a ligand-coated support, wherein said support is not a cell or bead, wherein the ligand comprises said antigen; and (iii) determining the level of activity of the simulated cells.
The specification does not provide a definition of the term “pharmaceutical grade”, only using the term in a single paragraph (page 2, line 30). As such, the term is interpreted broadly as encompassing any cell product that is intended for pharmaceutical use, i.e., for administration.
The “providing” and “stimulating” steps together are interpreted as broadly encompassing continuous incubation (e.g. culturing) of expanded cells with a ligand-coated support that is not a cell or bead, wherein the ligand is the antigen targeted by the CAR. This is because in continuous culture, the cells will activate and double (i.e., expand) multiple times, and thus previously expanded cells in culture will continue to be stimulated by the presence of the antigen that is coated to the support.
Bedoya teaches methods for “activation of immune cells by transiently expressing a Chimeric Antigen Receptor (CAR) molecule”, which “can be activated via ligand of the CAR molecule, e.g., a ligand of the CAR antigen binding domain (e.g., a cognate antigen molecule” (¶ 6). Bedoya further teaches that “[i]n embodiments, the ligand of the CAR molecule is present in/on (e.g., immobilized or attached to) a substrate, e.g., a non-naturally occurring substrate (¶ 7), and further where the substrate is “a solid support” chose from a group including a plate (¶ 23). Bedoya teaches that “the CAR-expressing immune cells are cultured in the presence of the ligand of the CAR molecule for a predetermined period” of hours or days, including “4 to 9 days” (¶ 25) and will undergo 3 or more doublings (¶ 26). Bedoya further teaches that the “immune effector cells are expanded and/or activated by culturing the immune cells in the presence of a ligand, e.g., a cognate antigen molecule” (¶ 58). Bedoya further teaches that the cells can be “expanded in culture for” several hours to “about 40 days” (¶ 431); i.e., continuous culture for multiple days. Bedoya additionally teaches that “[s]everal cycles of stimulation may also be desired such that culture time of immune effector cells, e.g., T cells, can be 60 days or more” (¶ 432). Bedoya further teaches that “[p]otency of the immune effector cells can be defined”, for example, “by various T cell functions”, for example, “cytokine production”, which “show at least a one, two, three, four, five, ten fold or more increase in pg/ml of proinflammatory cytokine production” (¶ 64). Bedoya further teaches a “method of treating a patient, comprising administering CAR-expressing cells manufactured as described above” and can be formulated in pharmaceutical compositions (¶ 685-686), which indicates that the cells are encompassed by the newly recited limitation that they are “pharmaceutical grade” (see above).
Thus, Bedoya teaches an in vitro method that meets the limitations of the claims as amended. The teachings of Bedoya that the CAR-expressing immune cells can be cultured for multiple days with the antigen-coated substrate (such as a plate), and will expand during this time, meets the limitations of the first two steps directed to providing a sample of pharmaceutical grade cell product that comprises activated and expanded immune cells expressing a CAR targeting an antigen and stimulating said cells by incubating said cells on a ligand-coated support wherein the ligand is an antigen binding to said CAR, because culturing the cells for multiple days will result in the cells being activated and expanded (i.e., doubled) and then contacting the antigen-coated support again. Furthermore, while this meets the limitations of these steps, Bedoya further teaches exposing the cells to “[s]everal cycles of stimulation”, which also meets the limitations of providing activated and expanded cells and then stimulating them with the antigen-coated support. Finally, the third step of the method is met by Bedoya’s further teachings that the potency of the immune cells can be defined, such as by measuring cytokine production.
Claims 2-4 each encompass the method of claim 1 wherein the CAR comprises an extracellular antigen-binding domain (ABD) binding specifically to a target antigen associated with disease state (claim 2), wherein the antigen is a tumor antigen (claim 3) or wherein the antigen is CD22 (claim 4), which is a tumor antigen. Bedoya further teaches that CAR can be an anti-CD22 CAR (¶ 34). As such, the teachings of Bedoya also anticipate claims 2-4.
Claim 6 encompasses a method of claim 1 wherein the cells express two or more CARs binding specifically to different target antigens associated with cancer. Bedoya further teaches that the cells can comprising a first and second CAR (e.g., ¶ 68-69) and further where each “targets a different cancer associated antigen” (¶ 83). As such, the teachings of Bedoya also anticipate claim 6.
Claim 7 encompasses a method of claim 6 wherein steps (i) to (iii) are performed with one ligand-coated support comprising a polypeptide comprising any one of the antigens targeted by said CARs. Such is met by the same teachings that meet the limitations of claims 1-4 and 6, where the one target antigen is CD22 as taught by Bedoya. As such, the teachings of Bedoya also anticipate claim 7.
Claims 8 and 9 encompass a method of claim 1 wherein the cells are T-cells. Bedoya further teaches that the cells are T-cells (e.g., see Abstract, ¶ 13). As such, the teachings of Bedoya also anticipate claims 8 and 9.
Claim 10 encompasses a method of claim 1 wherein said immune cells of step (i) are obtained from a patient that has been engineered ex vivo to express said CAR. Bedoya further teaches that the methods of the invention can be performed ex vivo (¶ 11). Bedoya also further teaches that the cells which are acquired and in which the CAR will be transiently expressed are “autologous to the subject who the cells will be administered to” (¶ 51), which indicates the method is performed ex vivo. As such, the teachings of Bedoya also anticipate claim 10.
Claim 11 encompasses a method of claim 1 wherein the activity level that is determined in step (iii) is cytokine secretion. As set forth above for claim, Bedoya teaches defining the potency of cytokine production, which is encompassed by determining the level of cytokine secretion. As such, the teachings of Bedoya also anticipate claim 11.
As such, while the amendments to the claims have been fully considered, it is found that the claims as amended are anticipated by the teachings of Bedoya.
Applicants’ arguments (5/29/26; pages 9-10) as they pertain to the rejection have been fully considered but are not found persuasive for the following reasons.
Applicants argue that the teachings of Bedoya directed to “activating/expanding immune cells” is “part of a production process of a medical product containing recombinant immune cells” and “a pharmaceutical product” will only be produced after having practiced the teachings of Bedoya (page 9). Applicants argue that the claimed methods are instead directed to “testing the quality of a pharmaceutical product obtained independently of the claimed method” (page 9). Applicants further argue that the claimed method is further distinguished from the teachings of Bedoya “with respect to the physiological state of the immune cells which are incubated with the ligand-coated support”. Applicants argue that in Bedoya, “the simulation step is carried out on immune cells having just been transduced with a CAR” and thus these cells “have not been activated/expanded yet”, whereas the claimed method on immune cells that are “already activated and expanded” (page 10). Applicants further argue that “Bedoya is not concerned with whether the proposed method of expanding the immune cells fulfills the quality criteria of the Regulatory Agencies necessary for validating a medicinal product (in a precise, specific, robust, and linear manner)” (page 10).
These arguments have been fully considered but are not found persuasive. With respect to the new limitation directed to a “pharmaceutical grade cell product”, as set forth above, the term “pharmaceutical grade” is not defined by the instant application. The term “pharmaceutical grade” in fact appears only once in the specification, in the background, in reference to “CAR T-cells products of pharmaceutical grade” (page 2, line 30). The term has thus been interpreted broadly to encompass any pharmaceutical use, i.e., administration, and as set forth above Bedoya teaches that the cells can be administered, and thus meet the limitation directed to “pharmaceutical grade”. With respect to the new limitation, directed to the “activated and expanded immune cells”, the restated rejection set forth above explains why the teachings of Bedoya still meet this limitation. With respect to whether the teaching of Bedoya concerns itself with fulfilling “the quality criteria of the Regulatory Agencies necessary for validating a medicinal product (in a precise, specific, robust, and linear manner)”, these attributes are not limitations of the claimed method as amended.
New rejections necessitated by Applicants’ amendment
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 8 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 pre-AIA the applicant regards as the invention.
In claim 8, the further limitation has been amended to change “said immune cell” (singular) to “said immune cells” (plural). However, the group from which the cells are selected is still directed to singular cells; i.e., “a T-cell, a NK-cell, and a macrophage”. It is unclear how “cells” can be selected from “a T-cell, a NK-cell, and a macrophage”. In this regard, the claim could be rendered definite by amending the recited group to recite, “T-cells, NK-cells and macrophages”. Compare with dependent claim 9, which recites that “said immune cells” are “T-cells”.
Claim Rejections - 35 USC § 112(a), written description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.-The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-4 and 6-11 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 because the claim contains new matter. 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 or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Per MPEP 2163, "New or amended claims which introduce elements or limitations that are not supported by the as-filed disclosure violate the written description requirement. See, e.g., In re Lukach, 442 F.2d 967, 169 USPQ 795 (CCPA 1971) (subgenus range was not supported by generic disclosure and specific example within the subgenus range); In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972) (an adequate description of a genus may not support claims to a subgenus or species within the genus)".
Claim 1 has been amended to limit the immune cells to those that are “a pharmaceutical grade cell product that comprises activated and expanded immune cells expressing a chimeric antigen receptor (CAR) targeting an antigen”. Applicants indicate that support for the amendments can be found throughout the specification, “for example at page 2, line 26, though page 3, line 19, as well as in Examples 5-7 on pages 41-42” (page 8). The only reference to a “pharmaceutical grade” product is on page 2 of the specification, in the Background, which refers to “CAR-T cells products of pharmaceutical grade”. This teaching is limited to T-cells, which is a single type of immune cell (i.e., a species) that differs in scope from that which is now claimed, which is directed to any immune cell (i.e., a genus). As such, amending the claims to be directed to a genus of pharmaceutical grade immune cells represents introduction of elements that are not supported by the as-filed disclosure, and thus represents new matter in violation of the written description requirement.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 ZACHARY C HOWARD whose telephone number is (571)272-2877. The examiner can normally be reached on Monday to Friday from 9 AM to 5 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford, can be reached at telephone number (571) 272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center for authorized users only. Should you have questions about access to Patent Center, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
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) Form at https://www.uspto.gov/patents/uspto-automated-interview-request-air-form.
/ZACHARY C HOWARD/Primary Examiner, Art Unit 1674
Prosecution Insights