DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant's amendment and remarks, filed 7/16/26, are acknowledged.
Claims 1, 5, 10-11 and 16 have been amended.
Claims 1, 5-16, 18-19, 23, 28-31, 35-39 are pending.
Claims 36-38 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention. Claims 7-9, 12, 18, 28, 30-31, 35 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention. It is noted that claim 16, as amended, now recites a step of differentiating the CD4+ Tscm cells into CD4+ specific T lineage cells, and the elected species of differentiation/lineage cells is a Treg differentiated with TGF-beta and IL-2. The elected species of disease, cancer, as it reads on the elected species of CD4+ T cell lineage (Treg) is free of the prior art. Therefore infections is also being included in the examination as a species of disease.
Claims 1, 5-6, 10-11, 13-16, 19, 23, and 39 are being acted upon.
The rejection of claims 1, 10-11, 13-16, 19, 23 and 29 under 35 U.S.C. 102/103 over WO2017/127755 has been withdrawn in view of Applicant’s claim amendments.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 39 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 39 depends from claim 36, which is directed to a pharmaceutic composition comprising a cell produced by the method of claim 1. However, the patentability of a product does not depend on its method of production. In other words, the process steps of claim 1 are not required elements in claim 36, since the claim could be infringed by a structurally identical cell produced by a different process. Therefore, claim 36 does not include all the limitations of the claim upon which it depends. As claim 39 depends from claim 36, it similarly does not include all the limitations of claim 1 from which it ultimately depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Applicant’s arguments filed 7/16/26 have been fully considered, but they are not persuasive.
Applicant argues that Claim 39 depends from claim 26, which is directed to a pharmaceutical composition comprising a cell produced by the method of claim 1. Applicant argues that since claim 39 is directed to a method of treatment comprising administering the composition of claim 36, it further limits claim 36.
This would be persuasive if claim 36 was an independent claim. However claim 36 (and hence claim 39) also depend from claim 1, which is directed to a method of producing the cell.
The issue is that claim 36 (and hence claim 39, which depends form claim 36) does not require all the limitations of claim 1. As noted above, the patentability of a product does not depend on its method of production. In other words, the process steps of claim 1 are not required elements in claim 36 or claim 39, since the claim could be infringed by a structurally identical cell produced by a different process. For example, claim 36 would encompass a structurally identical product produced by a completely different process than recited in claim 1, and claim 39 would encompass administering said product (produced by a different process) to treat cancer. Therefore, claim 39 does not require all the limitations of claim 1, from which it depends.
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 –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 1, 5-6 and 11 is/are rejected under 35 U.S.C. 102(a)(1) as anticipated by Gabrysova, 2011, as evidenced by Kleinewietfeld, 2013 (both of record).
Gabrysova teaches a method comprising culturing CD4+ T cells in vitro with an effective amount of MEK1/2 inhibitor PD0325901 (see Fig 3, in particular). Gabrysova teaches that the T cells are also cultured under Treg inducing conditions that include culture with IL-2 and TGF-beta for 7 days (see page 4296, in particular). The method is identical to that of the instant claims, and it would inherently produce CD4 T stem cell like memory CD44+CD62L+ T cells. . Regarding the limitation that the cells are multipotent, it is noted that the specification discloses that this encompass cells that are able to generate other CD4 T cell phenotypes after activation. As evidenced by Kleinewietfeld, T cells and Tregs are inherently “multipotent” in that they have plasticity to differentiate into other phenotypes after activation, such as Th1 and TH17 cells. Regarding step b) of claim 1, this would encompass the 7 day culture performed by Gabrysova. For example, the instant specification teaches that MEK inhibitors induce a stem cell like phenotype within 72 hours, and therefore the 7 day cultures of Gabrysova would inherently induce stem cell-like memory phenotypic cells in the first 72h (step a) that would be contacted with the differentiation inducing conditions for Treg differentiation during the remaining 4 days of the culture (step b).
Applicant’s arguments filed 7/16/26 have been fully considered, but they are not persuasive.
Applicant argues that Gabrysova does not disclose the method of claim 1, which as amended recites steps (a) and (b).
The instant specification discloses that CD4 T cells can be concurrently contacted with a MEK1/2 inhibit and cell lineage specific inducing conditions to generation one or more types of TSCM. See also Fig. 5, which shows that concurrent culture of T cells with MEK inhibitors and subset inducing conditions induces TSCM subtypes that differentiate into CD4 subtypes (result 2). In other words, concurrently performing steps a) and b) results in the generation of CD4 Tscm (i.e. multipotent cells) which differentiate into a CD4 subtype (Treg). The CD4 Tscm subtype cells depicted in Fig. 5 are “multipotent” since the specification discloses they would be capable to generate other CD4 T cell phenotypes after activation, given that Kleinewitfel teaches that even Tregs have plasticity to differentiation to other phenotypes after activation. Therefore, the present claims encompass the method of Gabryosova.
Amendment to the claims to recite step (a) contacting CD4+ T cells in vitro or ex vivo with an effective amount of an MEK1/2 inhibitor to produce CD4+TSCMcells, wherein the CD4+ TSCM cells are multipotent; and “subsequently” (b) contacting the multipotent CD4+ TSCM cells with cell-lineage specific inducing conditions to differentiate the multipotent CD4+ TSCM cells into one or more types of cells of CD4+ specific T cell-lineage would be remedial and would overcome the prior art of Gabryosova.
Claim 1, 5-6, 10-11, 13-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/127755, in view of WO2008/095141 and Davidson, 2007 (all of record).
WO 2017/127755 teaches a method of improving therapeutic potential of a T cell population by contacting the T cells in vitro or ex vivo with an agent from Table 1, wherein Table 1 discloses a MEK inhibitor (See pages 4-5, 7, and 47 in particular). WO 2017/127755 teaches that the T cells can be CD4+ T cells (see page 23, in particular). See also Table 1-2 and paragraph 131, wherein WO 2017/127755 discloses MEK inhibitor U0136 is disclosed as a modulator for CD4 T cells, in particular. Thus it would be obvious to use the MEK inhibiters for CD-4+ T cells based on the above teachings.
WO 2017/127755 also teaches that the method increases stem cell memory T cells (see page 46, in particular). WO 2017/127755 teaches that the methods increase cell potency and de-differentiation, with increased plasticity to differentiate into more cell types, i.e. multipotency (see paragraph 49 and102, in particular). WO 2017/127755 teaches that the T cells can express an exogenous nucleic acid encoding a CAR (see page 8 and 76, in particular). WO 2017/127755 teaches that the T cells have increased expression of CD62L (see page 14, in particular). WO 2017/127755 teaches that the MEK inhibitors include AZD6244, i.e. Selumetinib, see page 38, in particular. WO 2017/127755 teaches that the T cells can be expanded with anti-CD3 and anti-CD28 (see page 49, in particular). Regarding the recitation of a CD62L+CD44+ phenotype, this would be latent property of contacting CD4 T cells with a MEK inhibitor.
To summarize, WO 2017/127755 teaches producing CAR modified T cells, such as CD4+ T cells, wherein the cells are treated with various agents from Table 1, such as MEK inhibitors, to increase therapeutic potential of the T cells. The method of WO 2017/127755 is exemplified in Examples 13-14 wherein the reference discloses a process wherein CAR transduction procedure involves culture and expansion with the agent from Table 1 to provide for CAR CD4+ T cells with the improved properties.
The reference differs from the claimed invention in that it does not explicitly teach further contacting with Treg inducing conditions.
WO2008/095141 teaches that CD4+ Tregs can be engineered to express a CAR for redirecting the Tregs toward a desired antigen, and that the Tregs can be provided by introducing a CAR into (non-Treg) T cells, and thereafter inducing the T cells to differentiate into a Treg phenotype by exposure to TGF-beta (see page 18, in particular).
Davidson teaches that IL-2 is essential for TGF-beta mediated induction of Tregs and enhances Treg induction.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to further differentiate the CAR modified, MEK induced CD4 T cells taught by WO 2017/127755, to a Treg phenotype as taught by WO2008/095141. The ordinary artisan at the time the invention was made would have been motivated to do so with a reasonable expectation of success, because WO2008/095141 teaches that after transducing T cells to express a CAR, they can be induced to differentiate into CD4+ Tregs by culturing with TGF-beta, and that doing so can advantageously provide a CD4+ Treg redirected toward a desired antigen. It would also be obvious to include IL-2 in the Treg inducing cultures, since Davidson teaches that it is essential for TGF-beta mediated induction of Treg and enhances Treg induction.
Applicant’s arguments filed 7/16/26 have been fully considered, but they are not persuasive.
Applicant argues that WO 2017/127755 describes the use of a MEK inhibitor to impact signal transduction in cells, but that none of the cited references disclose producing Tcsm that are multipotent. Applicant argues that examples 13-14 involve culturing with different agents than MEK inhibitors.
WO 2017/127755 teaches a method of improving therapeutic potential of a CD4 T cell population by contacting the T cells in vitro or ex vivo with an agent from Table 1, wherein Table 1 discloses MEK inhibitors (See pages 4-5, 7, 23 and 47 in particular). WO 2017/127755 teaches that the method increases stem cell memory T cells and de-differentiation, with increased plasticity to differentiate into more cell types, i.e. multipotency (see page 46, paragraph 49 and102, in particular). See also Example 2, Table 2, wherein WO 2017/127755 discloses MEK inhibitor U0136 (MEK inhibitor) is disclosed as a modulator for CD4 T cells that induces a CCR7 and CD62L phenotype, i.e. Tcsm multipotent phenotype. WO 2017/127755 also teaches said cells engineered to express a CAR and producing said cells for adoptive therapy (examples 13-14 are cited as to the methodology for CAR introduction, which requires expansion with IL-2, anti-CD3, and anti-CD28). For example, see page 62, material and methods wherein the CAR are produced by expansion in the presence of the agent to improve their properties.
WO 2017/127755 explains that during manufacturing process for therapeutic CAR T cells, expansion and activation is required, but that process also drives differentiation to effector cell phenotype. WO 2017/127755 teaches that there is an urgent need in the art for methods useful for maintaining and expanding the desired immune cell subset by reducing cell differentiation during said CAR T cell manufacturing (see paragraph 6, in particular). Thus, on the whole WO 2017/127755 teaches a CAR T cell manufacturing process, wherein the expansion process required for CAR T cell production does not differentiate the cells into an effector phenotype, but rather keeps the cells in a de-differentiated state wherein the cells exhibit increased plasticity to differentiate into desired immune cell subset. WO 2017/127755 also teaches that the method can further comprise (b) isolating one or more desired subpopulations of the treated immune cells (See page 15). However, WO 2017/127755 does not specifically teach providing said subpopulation as a Treg by further contacting with Treg inducing conditions.
WO2008/095141 teaches that CD4+ Tregs can be engineered to express a CAR for redirecting the Tregs toward a desired antigen, and that the Tregs can be provided by introducing a CAR into (non-Treg) T cells, and thereafter inducing the T cells to into a Treg phenotype by exposure to TGF-beta (see page 18, in particular).
Davidson teaches that IL-2 is essential for TGF-beta mediated induction of Tregs and enhances Treg induction.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to isolate Treg cells, as the specific subpopulation in the method of WO 2017/127755, by further differentiating with TGF-beta and IL-2, as taught by WO2008/095141 and Davidson. One would recognize the advantages of using the MEK inhibitor during CAR T cell manufacturing to avoid differentiation to effector cells, as taught by WO 2017/127755, and to allow for plasticity to subsequently induce Treg phenotype after CAR T cell introduction, as taught by WO2008/095141.
The following are new grounds of rejection necessitated by Applicant’s claim amendments.
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.
Claims 16, 19, and 23 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 16 is directed to a treatment method comprising contacting CD4+ T cells under conditions to produce CD4+ Tscm cells that are multipotent, and contacting the multipotent Tscm cells with cell lineage specific inducing conditions to differentiate the multipotent CD4+ Tscm cells into one or more types of cells of “CD4+ specific T cell-lineage”. However, in the next step c), the claim recites administering “the CD4+ Tscm cells of a specific T cell lineage” to a subject. There is insufficient antecedent basis for “the CD4+ Tscm cells of a specific T cell lineage” in the claim. In the prior step, the cells are differentiated into “CD4+ specific T cell lineage” cells. This creates ambiguity in the claim, since it is not clear what cell is being administered. For example, the instant specification on page 1 discloses that CD4+ Tscm cells are further differentiated into one or more types of cells of CD4+ specific cell lineage that are selected from the group consisting of Tregs, Th1, Th2, and Th17 cells. Does the claim encompass administering said CD4+ specific cell lineage cells such as Tregs and Th1 cells, or do the claims require administering “CD4+ Tscm cells” as recited in amended step c)? For the purposes of examination, the claims are being interpreted as encompassing administering CD4+ specific T cell lineage cells, disclosed to encompass Tregs, Th1, Th2, and Th17 cells.
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 16, 19, 23, and 39 are rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. Specifically, the specification provides insufficient guidance to practice the invention as broadly claimed.
The specification disclosure is insufficient to enable one skilled in the art to practice the invention as claimed without an undue amount of experimentation. Undue experimentation must be considered in light of factors including: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill in the art, the level of predictability of the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention, see In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).
In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) states, “The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art.” “The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling” (MPEP 2164.03). The MPEP further states that physiological activity can be considered inherently unpredictable. With these teachings in mind, an enabling disclosure, commensurate in scope with the breadth of the claimed invention, is required.
Claim 16 and 39 are directed to a method for treating an infection or cancer in a subject, comprising differentiating CD4+ Tscm cells into “one or more types of CD4+ specific T cell-lineage” and administering the cells to the subject. The state of the art is such that Tscm cells produced by contact with MEK inhibitors can be administered to treat cancer or infection (see WO 2017/127755). However, the amended claim 16 and 39 require differentiating of said CD4+ Tcsm cells into one or more types of cells of CD4+ specific T cell lineage. This would encompass administering a wide range of CD4+ T cell types. For example, the claims would encompass treating infection or cancer by administering TH1 cells, Th17 cells, Th2, or Treg cells (See page 1 of the instant specification). The state of the art is such that treating cancer or infection with the genus of CD4+ subtypes encompassed by the instant claims is highly unpredictable. For example, Tregs are immunosuppressive and can inhibit anti-tumor immune responses (see Ahrends, 2018, of record). Likewise, while Tregs can be used to treat certain types of infection where the damage is caused by immunoinflammatory response to the infection agent, such as hepatitis C (see WO 2005070090), using Tregs to treat any infection would be highly unpredictable due to the immunosuppressive effects of Treg administration. Furthermore, the present claim encompass treating cancer with, for example Th2, cells, which is also highly unpredictable due to the potential to foster an immunosuppressive tumor microenvironment that can aid in tumor progression (see Chen, 2022).
Thus, based on the breadth of the claims and the unpredictability of the art, the instant specification must provide a sufficient and enabling disclosure commensurate in scope with the instant claims. No examples are guidance are provided for treating cancer or infection as broadly claimed with any CD4+ T cell lineage including, for example, Tregs or Th2 cells. Thus, based on the lack of guidance provided by the instant specification, the breadth of the claims, and the unpredictability of the art, it would require undue experimentation to practice the full scope of the claimed method.
Claim 16, 19, 23, and 39 rejected under 35 U.S.C. 103(a) as being unpatentable over WO 2017/127755, in view of WO2008/095141 and Davidson, 2007, as applied to claim to claim 1 above, and further in view of WO2005070090.
The combined teachings of WO 2017/127755, WO2008/095141 and Davidson, are discussed above.
They do not teach administering Tregs to treat infection.
WO2005070090 teaches that Treg therapy can be used to treat infections that that cause tissue damage due to immunoinflammatory response to the infectious agents, such as hepatitis C (see page 9, in particular).
Therefore, it would have been obvious to a person of ordinary skill in the art at the time the invention was made to apply the teachings of WO2005070090, the method of producing Tregs made obvious by WO 2017/127755, WO2008/095141 and Davidson. One of ordinary skill in the art at the time the invention was made would have been motivated to do so, and have a reasonable expectation of success, because WO2005070090 teaches that Treg therapy can be used for infections that that cause tissue damage due to immunoinflammatory response to the infectious agents, such as hepatitis C. It would also be obvious to further administer an additional treatment suitable for use for hepatitis C to enhance treatment outcomes. Alternatively, WO2008/095141 also teaches that the Tregs can be administered in combination with cytokines to maintain the Tregs in the recipient (see page 39, i.e. a second therapeutic agent).
No claim is 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY E JUEDES whose telephone number is (571)272-4471. The examiner can normally be reached on M-F from 7am to 3pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached on 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Amy E. Juedes
Patent Examiner
Technology Center 1600
/AMY E JUEDES/Primary Examiner, Art Unit 1644
