DETAILED ACTION
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 .
Priority
The instant application is a national stage entry under 35 USC 371 of PCT/US2021/057152, filed
28 October 2021. Acknowledgment is made of Applicant’s claim for benefit under 35 USC 119(e) to US Provisional Application No. 63106591, filed 28 October 2020.
Status of the Claims
Applicant’s preliminary submission filed 25 October 2023 has been entered. Claims 1-32, 35-36, and 39-40 are pending. Claims 3, 5-6, 8, 11-15, 17, 19, 21, 23, 25, 27, 29-31, 35, and 39-40 have been amended, while claims 33-34 and 37-38 have been cancelled without prejudice or disclaimer. Prosecution on the merits commences for claims 1-32, 35-36, and 39-40.
Drawings
The drawings are objected to for comprising a template page for Figures 3-9, 11-12, 14-15, 17-18, 22, and 27 prior to the disclosure of the individual figures instead of labeling the individual figures themselves accordingly. For instance, when looking at Figure 3, the template for Figure 3 indicates that there are four figures associated with the figure: Fig. 3-1, Fig. 3-2, Fig. 3-3, and Fig. 3-4. However, the individual figures of Figure 3 on Pages 4-7 of the drawings filed 18 April 2023 are not labeled as Fig. 3-1, Fig. 3-2, Fig. 3-3, and Fig. 3-4. Therefore, the Examiner proposes removing the template page for each of the aforementioned figures and instead labeling each individual figure as “Fig. 3-1”, etc.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The substitute Specification filed 18 April 2023 is acknowledged and entered into the application file.
Claim Objections
Claim 28 is objected to because of the following informalities:
Regarding claim 28: The instant claim is objected to for reciting “wherein the starting population of cells comprise a null mutation in a gene selected from”, instead of “wherein the starting population of cells comprise a null mutation in a gene selected from the group consisting of”.
Appropriate correction is required.
Claim Interpretation
Under the broadest reasonable interpretation of each claim, all of the “optional” limitations are not required.
Furthermore, instant claims 30-31 and 35 are directed to a population of cells enriched for CD4 single positive cells, CD4+ Teff cells, or CD4+ Treg cells, respectively, each obtained by the method of claim 1. These are product-by-process limitations. Product-by-process limitations are considered only in so far as the method of production affects the structure of the final product. In the instant case, there is no evidence that the production method of instant claim 1 imparts any particular structure or significance to the enriched CD4 single positive cells, CD4+ Teff cells, or CD4+ Treg cells. Thus, the claim will be interpreted as if the CD4+ cell types derived from any source or production method fulfills the recited claim limitations. See MPEP § 2113.
Claim Rejections - 35 USC § 112
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 12-14 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.
Regarding claim 12: The instant claim recites the limitation "the CD4 single positive Teff or Treg cells" in Line 2. There is insufficient antecedent basis for this limitation in the claim, as there is no prior recitation of CD4 single positive Teff cells or CD4 single positive Treg cells within the instant claim or parent claim 1.
Appropriate correction is required.
For purposes of compact prosecution, the instant claim will be interpreted as if the CD4 single positive cells are isolated from culture by FACS.
Regarding claim 13: The instant claim recites the limitation "the CD4 single positive Teff or CD4+CD25+CD127low Treg cells" in Line 2. There is insufficient antecedent basis for this limitation in the claim, as there is no prior recitation of CD4 single positive Teff cells or CD4+CD25+CD127low Treg cells within the instant claim or parent claim 1.
Appropriate correction is required.
For purposes of compact prosecution, the instant claim will be interpreted as if the CD4 single positive cells are isolated from culture by FACS.
Regarding claim 14: The instant claim recites the limitation "the CD4+CD25highCD127low and CD4+CD25lowCD127low Treg cells" in Line 2. There is insufficient antecedent basis for this limitation in the claim, as there is no prior recitation of CD4+CD25highCD127low Treg cells or CD4+CD25lowCD127low Treg cells within the instant claim or parent claim 1.
Appropriate correction is required.
For purposes of compact prosecution, the instant claim will be interpreted as if the CD4 single positive cells are isolated from culture by FACS.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 30-31, 35, and 40 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a nature-based product without significantly more.
Claims 30-31 and 35 are directed to populations of cells enriched for CD4 single positive cells (claim 30), CD4+ Teff cells (claim 31), or CD4+ T reg cells (claim 35) obtained by the method of claim 1. Each of instant claims 30-31 and 35 comprises a product-by-process limitation, as can be observed in the Claim Interpretation section above and is incorporated in its entirety herein. Claim 40 is directed to a pharmaceutical composition comprising the population of cells of claim 30 and a pharmaceutically acceptable carrier, and thereby fully incorporates the product-by-process limitation of instant claim 30.
The test for 101 eligibility of judicial exceptions can be found at MPEP § 2106:
“First, the claimed invention must be to one of the four statutory categories. 35 U.S.C. 101 defines the four categories of invention that Congress deemed to be the appropriate subject matter of a patent: processes, machines, manufactures and compositions of matter.”
“Second, the claimed invention also must qualify as patent-eligible subject matter, i.e., the claim must not be directed to a judicial exception unless the claim as a whole includes additional limitations amounting to significantly more than the exception. The judicial exceptions (also called "judicially recognized exceptions" or simply "exceptions") are subject matter that the courts have found to be outside of, or exceptions to, the four statutory categories of invention, and are limited to abstract ideas, laws of nature and natural phenomena (including products of nature). Alice Corp. Pty. Ltd. v. CLS Bank Int'l, 573 U.S. 208, 216, 110 USPQ2d 1976, 1980 (2014) (citing Ass'n for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 589, 106 USPQ2d 1972, 1979 (2013).”
“The Supreme Court in Mayo laid out a framework for determining whether an applicant is seeking to patent a judicial exception itself, or a patent-eligible application of the judicial exception. See Alice Corp., 573 U.S. at 217-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. 66, 101 USPQ2d 1961). This framework, which is referred to as the Mayo test or the Alice/Mayo test, is discussed in further detail in subsection III, below. The first part of the Mayo test is to determine whether the claims are directed to an abstract idea, a law of nature or a natural phenomenon (i.e., a judicial exception). Id. If the claims are directed to a judicial exception, the second part of the Mayo test is to determine whether the claim recites additional elements that amount to significantly more than the judicial exception. Id. citing Mayo, 566 U.S. at 72-73, 101 USPQ2d at 1966). The Supreme Court has described the second part of the test as the "search for an 'inventive concept'". Alice Corp., 573 U.S. at 217-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. at 72-73, 101 USPQ2d at 1966).”
Examiners should determine whether a claim satisfies the criteria for subject matter eligibility by evaluating the following steps outlined in a flow chart at MPEP 2106(III) and 2106.04(II)(A):
Step 1: is the Claim to a process, machine, manufacture or composition of matter? If Yes, proceed to Step 2A;
Step 2A, prong one: Is the Claim directed to a law of nature, a natural phenomenon (product of nature), or an abstract idea? If Yes, proceed to Step 2A, prong two;
Step 2A, prong two: Does the claim recite additional elements that integrate the judicial exception into a practical application? If No, proceed to Step 2B;
Step 2B: Does the claim recite additional elements that amount to significantly more (an inventive concept) than the judicial exception? If No, the claim is not eligible subject matter under 35 USC 101.
With regard to Step 1: YES, the claims are each directed to a composition of matter, or product.
With regard to Step 2A, prong one: YES, the claims are directed to an enriched population of CD4 single positive cells (claim 30), CD4+ Teff cells (claim 31), or CD4+ T reg cells (claim 35), which are nature-based products. More specifically, since the instantly claimed CD4+ cell types comprise product-by-process limitations – see Claim Interpretation section above – the claimed CD4+ cells are compared to the closest naturally occurring counterpart, which are each of CD4 single positive cells, CD4+ Teff cells, and CD4+ T reg cells, per se. Thus, there is no marked different between the claim and product of nature. See, for example, Paragraphs [0002]-[0003] of Conway et al (WO 2021/092581 A1, of record on IDS filed 23 July 2024). The same is true for the pharmaceutical composition comprising the CD4 single positive cells.
With regard to Step 2A, prong two: No, the claims do not include any additional elements that integrate the judicial exceptions into a practical application. Integration into a practical application requires additional elements in the claim to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such that the claim is more than a drafting effort designed to monopolize the exception.
The claims do not modify or transform the naturally occurring CD4+ cell types, nor apply the cells for a particular treatment or medical condition, nor imposes a meaningful limit on the cells recited therein. It is of note that the incorporation of the naturally occurring CD4+ cells in a pharmaceutical composition also does not modify or transform the naturally occurring CD4+ cells, nor apply the cells for a particular treatment or medical condition, nor imposes a meaningful limit on the cells recited therein.
With regard to Step 2B: No, the claim does not provide any additional elements that amount to significantly more (an inventive concept) than the judicial exception.
Taken together, the claims each encompass a natural product. The judicial exceptions are not integrated into practical applications as iterated above. The claims do not include additional elements
that are sufficient to amount to significantly more than the judicial exception as iterated above.
Claim Rejections - 35 USC § 102
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 (i.e., changing from AIA to pre-AIA ) 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.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-7, 12-14, and 30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Takahama et al (J Immunol, 1996, of record on IDS filed 10 July 2025).
Takahama et al disclose the culture of CD4+CD8+ T cells in a culture medium comprising PMA and ionomycin for five days, wherein CD4+ T cells are subsequently isolated from culture using FACS (Pages 1508-1511; Figures 1-2, 4; Table 1). Takahama et al further disclose that the PMA is at a concentration of 0.016 to 0.16 μM, and ionomycin is at a concentration of 0.13 to 1.3 μM (Pages 1509-1510; Figure 4).
Accordingly, Takahama et al anticipate the claims as follows:
Regarding claims 1, 5, 12-14, and 30: Instant claim 30 comprises product-by-process. The effect of the product-by-process language is discussed above – see Claim Interpretation – and is incorporated herein in its entirety. Furthermore, the claim interpretation of instant claim 12-14 can be observed above in the 35 USC 112(b) section and is incorporated in its entirety herein.
Accordingly, Takahama et al disclose the culture of CD4+CD8+ T cells in a culture medium comprising PMA and ionomycin for five days (claim 5), wherein CD4+ T cells are subsequently isolated from culture using FACS (claims 12-14). This therefore reads on the method of instant claim 1 and population of instant claim 30.
Regarding claims 2-4: Following the discussion of claim 1, Takahama et al further disclose that the PMA is at a concentration of 0.016 to 0.16 μM, and ionomycin is at a concentration of 0.13 to 1.3 μM. As these molarity ranges encompass a PMA concentration of 0.00625 μg/ml and an ionomycin concentration of 0.125 μg/ml (see calculations provided on Page 2 of third party observation for application number EP 2021810847.0, of record on IDS filed 10 July 2025), this therefore has a weight ratio of PMA to ionomycin of 1:20 (claim 3) and reads on the methods of instant claims 2 and 4. See MPEP § 2131.03.
Regarding claims 6-7: As aforementioned in the discussion of claim 1, Takahama et al disclose the culture of CD4+CD8+ T cells in a culture medium comprising PMA and ionomycin for five days, wherein CD4+ T cells are subsequently isolated from culture using FACS. As these are the same method steps as provided in instant claim 1, the method of Takahama et al will inherently result in the generation and isolation of immature CD4+ effector T cells (claim 7). This therefore reads on the method of instant claim 6. See MPEP § 2112.
Claims 1, 3, 6-7, 12-16, 27-28, 30-32, and 40 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Kaneko et al (US 2022/0411752 A1). Kaneko et al has an effective filing date of 01 November 2019.
Kaneko et al disclose methods for producing an IL-4 non-secreting and IFN-γ secreting (Th1-type)
or IFN-γ non-secreting and IL-4 secreting (Th2-type) CD4 single-positive T cell (CD4SP T cell) (Abstract).
As such, Kaneko et al disclose the generation of an artificial thymic organoid (ATO) from T-iPSC-derived HSPCs, wherein the ATOs produce CD4+CD8+ T cells that are cultured in medium comprising PMA and ionomycin (Paragraphs [0003], [0005], [0013], [0064], [0066], [0078], [0080], [0133]-[0147], [0168]-[0169], [0187]-[0199]). Kaneko et al further disclose that the iPSC is a universalized iPSC wherein an HLA gene has been knocked out (Paragraph [0133]).
Kaneko et al further disclose that CD4+ T cells are isolated from culture via FACS (Paragraphs [0169], [0199]).
Kaneko et al further disclose that the cells of the ATO – including the CD4+CD8+ T cells – are primary human cells (Paragraphs [0003], [0107]-[0108], [0130]).
Kaneko et al further disclose a pharmaceutical composition comprising the isolated Th1-type or Th2-type CD4+ T cells and a pharmaceutically acceptable carrier for the treatment of a subject suffering from an autoimmune disease (Paragraphs [0002], [0016], [0097], [0179]-[0180], [0184]-[0185]).
Accordingly, Kaneko et al anticipate the claims as follows:
Regarding claims 1, 15-16, and 30: Instant claim 30 comprises product-by-process. The effect of the product-by-process language is discussed above – see Claim Interpretation – and is incorporated herein in its entirety.
Accordingly, Kaneko et al disclose a method of isolating CD4+ T cells, wherein T-iPSC (claims 15-16)-derived HSPCs form an ATO that produces CD4+CD8+ T cells, which are then cultured in medium comprising PMA and ionomycin, and sorted for CD4+ T cells. This therefore reads on the method of instant claim 1 and population of instant claim 30.
Regarding claim 3: Following the discussion of claim 1, Kaneko et al further disclose that the concentration of PMA in culture is 0.04 μg/ml, while the concentration of ionomycin is 4 μg/ml (Paragraph [0199]). As this results in a weight ration of PMA to ionomycin of 1:100, this therefore reads on the method of the instant claim.
Regarding claims 6-7: As aforementioned in the discussion of claim 1, Kaneko et al disclose the culture of CD4+CD8+ T cells in a culture medium comprising PMA and ionomycin, wherein CD4+ T cells are subsequently isolated from culture. As these are the same method steps as provided in instant claim 1, the method of Kaneko et al will inherently result in the generation and isolation of immature CD4+ effector T cells (claim 7). This therefore reads on the method of instant claim 6. See MPEP § 2112.
Regarding claims 12-14: Following the discussion of claim 1, Kaneko et al further disclose that CD4+ T cells are isolated from culture via FACS. This therefore reads on the method of the instant claims given the interpretation provided in the 35 USC 112(b) section above.
Regarding claim 27: Following the discussion of claim 1, Kaneko et al further disclose that the cells of the ATO – including the CD4+CD8+ T cells – are primary human cells. This therefore reads on the method of the instant claim.
Regarding claim 28: Following the discussion of claim 27, Kaneko et al further disclose that the iPSC is a universalized iPSC wherein an HLA gene has been knocked out. This therefore reads on the method of the instant claim, as the cells of the ATO – including the CD4+CD8+ T cells – will also have an HLA gene knocked out, as evidenced by Paragraphs [0193]-[0197].
Regarding claims 31-32: Kaneko et al disclose the treatment of a subject suffering from an autoimmune disease via the administration of the Th1-type or Th2-type CD4+ T cells – which are CD4+ T effector cells – to the subject in need thereof. This therefore reads on the population of instant claim 31 and method of instant claim 32.
Regarding claim 40: Kaneko et al disclose a pharmaceutical composition comprising the isolated Th1-type or Th2-type CD4+ T cells and a pharmaceutically acceptable carrier. This therefore reads on the pharmaceutical composition of the instant claim.
Claims 35-36 and 39 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Gorochov et al (WO 2013/050596 A1).
Gorochov et al disclose CD4+ regulatory T cells that are administered to a patient suffering from an autoimmune disease (Abstract; Pages 1, 3-4, 10).
Accordingly, Gorochov et al anticipate the claims as follows:
Regarding claims 35-36 and 39: Instant claim 30 comprises product-by-process. The effect of the product-by-process language is discussed above – see Claim Interpretation – and is incorporated
herein in its entirety.
Accordingly, Gorochov et al disclose CD4+ regulatory T cells (claim 35) that are administered to a patient suffering from an autoimmune disease (claim 39). This therefore reads on the method of instant claim 36.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 6-8, 10-16, 27-28, 30-32, 35-36, and 39-40 are rejected under 35 U.S.C. 103 as being unpatentable over Kaneko et al (US 2022/0411752 A1) in view of Schmidt et al (PLoS One, 2016).
The discussion of Kaneko et al regarding claim 1 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Kaneko et al anticipate claims 1, 3, 6-7, 12-16, 27-28, 30-32, and 40. Schmidt et al is considered prior art under 35 USC 102(a)(1).
Regarding claims 8, 11, and 35: Following the discussion of claim 15, Kaneko et al further suggest the induction of the Th1-type or Th2-type CD4+ T cells into regulatory T cells (Tregs) for the treatment of allergic and autoimmune diseases (Paragraph [0002]).
Kaneko et al do not disclose that the Th1-type or Th2-type CD4+ T cells are further cultured in a second medium comprising TGF-β and all trans-retinoic acid (ATRA) to thereby obtain a population of Tregs, as required by instant claim 8.
Schmidt et al, however, disclose a method of inducing Tregs, wherein CD4+ T cells are cultured in the medium comprising TGF-β and ATRA for six days (Abstract; Pages 4, 20; Figure 1).
Therefore, it would have been prima facie to modify the method of Kaneko et al such that the CD4+ T cells are cultured in medium comprising TGF-β and ATRA to obtain a population of Tregs, as detailed in Schmidt et al. One of ordinary skill in the art would have been motivated to utilize a culture medium composition that is known to generate Tregs, and would have had a reasonable expectation of success given the disclosure of Schmidt et al. See MPEP § 2143(I)(G).
Consequently, Kaneko et al as modified by Schmidt et al render obvious a method of generating Tregs (claim 35), wherein the CD4+ T cells are cultured in medium comprising TGF-β and ATRA for six days (claim 11). This therefore renders obvious the method of instant claim 8.
Regarding claim 10: Following the discussion of claim 8, Schmidt et al further disclose that the medium comprising TGF-β and ATRA is serum-free X-Vivo 15 medium, which is for the culture of the T cells (Page 20). This therefore reads on the method of the instant claim.
Regarding claims 36 and 39: Following the discussion of claim 35, Kaneko et al further suggest the use of Tregs as therapeutics for autoimmune diseases (Paragraph [0002]). Therefore, the ordinary artisan would have been motivated to utilize the generated CD4+ Tregs rendered obvious by Kaneko et al as modified by Schmidt et al for the treatment of an autoimmune disease (claim 39), and would have had a reasonable expectation of success given that Kaneko et al disclose the use of CD4+ T cells for the treatment of autoimmune diseases (Paragraphs [0002], [0016], [0097], [0179]-[0180], [0184]-[0185]). See MPEP § 2143(I)(G). This therefore renders obvious the method of instant claim 36.
Claims 1, 3, 6-16, 27-28, 30-32, 35-36, and 39-40 are rejected under 35 U.S.C. 103 as being unpatentable over Kaneko et al (US 2022/0411752 A1) in view of Schmidt et al (PLoS One, 2016), and further in view of Gorochov et al (WO 2013/050596 A1).
The discussion of Kaneko et al regarding claim 1 and Kaneko et al as modified by Schmidt et al
regarding claim 8 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Kaneko et al anticipate claims 1, 3, 6-7, 12-16, 27-28, 30-32, and 40. Kaneko et al as modified by Schmidt et al render obvious claims 1, 3, 6-8, 10-16, 27-28, 30-32, 35-36, and 39-40. Gorochov et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2).
Regarding claim 9: As aforementioned in the discussion of claim 8, Kaneko et al as modified by Schmidt et al render obvious a method of generating Tregs, wherein the CD4+ T cells are cultured in medium comprising TGF-β and ATRA.
Schmidt et al further disclose that the medium can further comprise IL-2, an anti-CD3 antibody, and an anti-CD28 antibody, wherein the anti-CD3 and anti-28 antibodies are utilized to stimulate the CD4+ T cells (Page 20).
The combination of Kaneko et al and Schmidt et al fail to teach that the medium further comprises an anti-CD2 antibody, as required by instant claim 9.
Gorochov et al, however, disclose the stimulation of Tregs with anti-CD3, anti-CD28, and anti-CD2 antibodies (Pages 5-6, 12-13).
Therefore, it would have been prima facie to modify the method of Kaneko et al in view of Schmidt et al such that the culture medium further comprises an anti-CD2 antibody, as detailed in Gorochov et al. One of ordinary skill in the art would have been motivated to strength the stimulation of the CD4+ T cells via the addition of the anti-CD2 antibody (Gorochov et al: Pages 5-6), and would have had a reasonable expectation of success given that the disclosures of Schmidt et al and Gorochov et al are concerned with the generation and maintenance of CD4+ Tregs. See MPEP § 2143(I)(G).
Consequently, Kaneko et al as modified by Schmidt et al and Gorochov et al render obvious a method of generating Tregs, wherein the CD4+ T cells are cultured in medium comprising TGF-β, ATRA, IL-2, an anti-CD2 antibody, an anti-CD3 antibody, and an anti-CD28 antibody. This therefore renders obvious the method of the instant claim.
Claims 1, 3, 6-7, 12-18, 23, 25, 27-32, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Kaneko et al (US 2022/0411752 A1) in view of Gschweng et al (US 2021/0040449 A1).
The discussion of Kaneko et al regarding claims 1 and 15 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Kaneko et al anticipate claims 1, 3, 6-7, 12-16, 27-28, 30-32, and 40. Gschweng et al is considered prior art under 35 USC 102(a)(2), with an effective filing date of 16 February 2018.
Regarding claims 17 and 25: Following the discussion of claim 15, Kaneko et al further suggest the induction of the Th1-type or Th2-type CD4+ T cells into regulatory T cells (Tregs) for the treatment of allergic and autoimmune diseases (Paragraph [0002]).
Kaneko et al do not disclose that the iPSCs comprise a heterologous transgene sequence encoding a lineage commitment factor that promotes the differentiation of the iPSCs to CD4+ Tregs, as required by instant claim 17.
Gschweng et al, however, disclose the genetic engineering of iPSCs such that the iPSCs comprise essential cell fate regulators that promote the differentiation of the iPSCs into different T-cell lineages, including FOXP3 for the induction of Tregs (Paragraphs [0065]-[0095], [0268]-[0269], [0309]).
Therefore it would have been prima facie obvious to have modified the method of Kaneko et al such that starting population of iPSCs comprises a FOXP3 transgene that promotes the differentiation of the iPSCs to CD4+ Tregs, as detailed in Gschweng et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to modify the iPSCs to ensure commitment to the Treg lineage, as that is the final desired cellular therapeutic product for the treatment of autoimmune diseases (Kaneko et al: Paragraph [0002]; Gschweng et al: Paragraphs [0271], [0288]-[0289]), and would have had a reasonable expectation of success since both Kaneko et al and Gschweng et al are concerned with the generation of CD4+ T cells from the iPSC-derived ATOs (Kaneko et al: Paragraphs [0003], [0005], [0013], [0064], [0066], [0078], [0080], [0133]-[0147], [0168]-[0169], [0187]-[0199]; Gschweng et al: Paragraphs [0262]-[0267]). See MPEP § 2143(I)(G).
Consequently, Kaneko et al as modified by Gschweng et al render obvious a method of generating a CD4+ Treg, wherein the starting population of iPSCs is genetically engineered to comprise a heterologous FOXP3 (claim 25) sequence in the genome. As FOXP3 is a lineage commitment factor that promotes the differentiation of the iPSCs to CD4+ Tregs, this therefore renders obvious the method of the instant claim.
Regarding claims 18 and 23: Following the discussion of claim 1, Gschweng et al further disclose that exogenous protein sequences are integrated into the genome of the iPSCs at a TRAC gene locus (claim 23), wherein the exogenous protein sequence is under control of the endogenous promoter of the gene locus (Paragraphs [0030], [0032], [0057], [0106], [0180], [0206]-[0209], [0215], [0217], [0251]). Therefore, the ordinary artisan would have been motivated to insert the heterologous FOXP3 sequence into the TRAC gene locus such that the FOXP3 sequence is under control of the endogenous TRAC promoter, as doing so would have allowed for the promotion of the iPSCs towards Tregs while also preventing the host immune reactivity to the cells (Gschweng et al: Paragraph [0008]), and would have had a reasonable expectation of success given the disclosure of Gschweng et al. See MPEP § 2143(I)(G). This therefore renders obvious the method of instant claim 18.
Regarding claim 29: Following the discussion of claim 1, Gschweng et al further disclose that the engineered cells further comprise a suicide gene (Paragraphs [0016], [0053], [0198], [0224]-[0227]). As the engineered cells can comprise CD4+CD8+ T cells (Paragraphs [0016], [0033], [0063]-[0064], [0071], [0139]), this therefore renders obvious the method of the instant claim for the same reasons as discussed in the rejection of claim 17.
Claims 1, 3, 6-7, 12-32, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Kaneko et al (US 2022/0411752 A1) in view of Gschweng et al (US 2021/0040449 A1), and further in view of Burleigh et al (WO 2019/195491 A1).
The discussion of Kaneko et al regarding claims 1 and 15 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. The discussion of Kaneko et al as modified by Gschweng et al regarding claims 17, 23, and 25 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Kaneko et al anticipate claims 1, 3, 6-7, 12-16, 27-28, 30-32, and 40. Kaneko et al as modified by Gschweng et al render obvious claims 1, 3, 6-7, 12-18, 23, 25, 27-32, and 40. Burleigh et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2).
Regarding claims 19-20: Following the discussion of claim 17, Gschweng et al further disclose that the engineered stem cells further comprise a chimeric antigen receptor (CAR) that is integrated into the TRAC gene locus (Paragraphs [0085], [0087], [0094], [0096], [0114], [0214]-[0217]).
The combination of Kaneko et al and Gschweng et al fail to teach that coding sequences for the FOXP3 sequence and CAR are separated by an in-frame coding sequence for a self-cleaving peptide or by an IRES, as required by instant claim 20.
Burleigh et al, however, disclose the engineering of iPSC-derived T cells, wherein a template polynucleotide comprising one or more transgenes separated by an in-frame 2A self-cleavage peptide sequence is knocked into a TRAC gene locus of the cells, wherein the transgenes include a CAR or any polypeptide in which expression in the cell is desired (Paragraphs [0036]-[0038], [0045]-[0046], [0171], [0445], [0504]-[0505], [0510]-[0511], [0522]-[0524], [0529], [0538]-[0539]). Burleigh et al further disclose that the cell can further comprise a recombinant FOXP3 (Paragraph [0577]).
Therefore, it would have been prima facie obvious to have further modified the method of Kaneko et al in view of Gschweng et al such that the starting population of iPSCs is engineered to comprise a transgene comprising a FOXP3 coding sequence and CAR, wherein the FOXP3 coding sequence and CAR are separated by an in-frame 2A self-cleavage peptide sequence, as detailed in Burleigh et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to employ a technique that is well-known in the art to integrate multiple coding sequences of a transgene into a TRAC gene locus, and would have had a reasonable expectation given the disclosure of Burleigh et al. See MPEP § 2143(I)(A) and MPEP § 2143(I)(G).
Consequently, Kaneko et al as modified by Gschweng et al and Burleigh et al render obvious a method of generating CD4+ Tregs, wherein the starting population of iPSCs is genetically engineered to comprise a transgene comprising a heterologous FOXP3 sequence and CAR (claim 20) that are separated by an in-frame 2A self-cleavage peptide sequence. This therefore renders obvious the method of instant claim 19.
Regarding claim 21: Following the discussion of claim 17, Burleigh et al further disclose that a ribosome skipping element/self-cleavage element, such as a 2A element, is placed immediately upstream of the transgene coding sequence, such that the ribosome skipping element/self-cleavage element is placed in-frame with the endogenous gene (Paragraphs [0505]-[0508], [0551]). This therefore renders obvious the method of the instant claim for the same reasons as detailed in the rejection of instant claim 19.
Regarding claims 22 and 24: Following the discussion of claim 21, Burleigh et al further disclose that transgene sequence is integrated downstream of the most 5' nucleotide of exon 1 and upstream of the most 3' nucleotide of exon 1 (claim 24) of the open reading frame of the endogenous TRAC locus (Paragraphs [0013], [0058]-[0059], [0103], [0113]-[0114], [0153], [0160], [0203]-[0204], [0252], [0442], [0451], [0501]. With that, Burleigh et al further disclose that the transgene includes a recombinant TRAC that can comprise functional exonic sequences (Paragraphs [0096], [0153], [0160], [0169], [0193], [0196], [0416], [0447]-[0451], [0456], [0556]. This therefore renders obvious the method of instant claim 22 for the same reasons as detailed in the rejection of instant claim 19.
Regarding claim 26: Following the discussion of claim 25, Gschweng et al further disclose that the cell fate regulators can be FOXP3 and ThPOK (Paragraphs [0066], [0089], [0094], [0310]). This therefore renders obvious the method of the instant claim for the same reasons as discussed in the rejection of claim 19, as the ordinary artisan would have been motivated to drive the starting population of iPSCs of Kaneko et al towards the intermediate product of a Th1-type CD4+ T cell and end product of a CD4+ Treg. See MPEP § 2143(I)(G).
Claims 1, 3, 6-7, 12-32, 35-36, and 39-40 are rejected under 35 U.S.C. 103 as being unpatentable over Kaneko et al (US 2022/0411752 A1) in view of Conway et al (WO 2021/092581 A1, of record on IDS filed 23 July 2024).
The discussion of Kaneko et al regarding claims 1 and 15 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Kaneko et al anticipate claims 1, 3, 6-7,
12-16, 27-28, 30-32, and 40. Conway et al is considered prior art under 35 USC 102(a)(2).
However, the applied reference of Conway et al has a common assignee and joint inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Regarding claims 17-21, 23-26 and 35: Following the discussion of claim 15, Kaneko et al further suggest the induction of the Th1-type or Th2-type CD4+ T cells into regulatory T cells (Tregs) for the treatment of allergic and autoimmune diseases (Paragraph [0002]).
Kaneko et al do not disclose that the iPSCs comprise a heterologous transgene sequence encoding a lineage commitment factor that promotes the differentiation of the iPSCs to CD4+ Tregs, as required by instant claim 17.
Conway et al, however, disclose genetically engineered mammalian stem and progenitor cells that have increased potential to differentiate into regulatory T cells (Abstract).
As such, Conway et al disclose a genetically engineered iPSC comprising a heterologous sequence in the genome, wherein the heterologous sequence is integrated in exon 1, 2, or 3 of the TRAC gene locus and comprises a transgene encoding sequences for FOXP3 and ThPOK, wherein the two coding sequences are in-frame and are separated by an in-frame coding sequence for a self-cleaving peptide, and an IRES immediately upstream of the transgene (Paragraphs [0007], [0010]-[0012], [0019], [0023], [0035], [0039], [0043]-[0044]; Figure 6). It is of note that FOXP3 and ThPOK are both lineage commitment factors that promote the differentiation of the iPSCs to CD4+ Tregs (Paragraphs [0033], [0039]).
Therefore, it would have been prima facie obvious to have modified the method of Kaneko et al such that the starting population of iPSCs is genetically modified to comprise a transgene encoding sequences for FOXP3 and ThPOK, as detailed in Conway et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to modify the iPSCs to ensure commitment to the Treg lineage, as that is the final desired cellular therapeutic product for the treatment of autoimmune diseases (Kaneko et al: Paragraph [0002]; Conway et al: Paragraphs [0091]-[0092]), and would have had a reasonable expectation of success since the disclosures of both Kaneko et al and Conway et al are concerned with the differentiation of iPSCs into CD4+ Tregs. See MPEP § 2143(I)(G).
Consequently, Kaneko et al as modified by Conway et al render obvious a method of generating CD4+ Tregs (claim 35), wherein the starting population of iPSCs is genetically engineered to comprise a heterologous sequence in the genome, wherein the heterologous sequence is integrated in exon 1, 2, or 3 of the TRAC gene locus (claims 18, 23-24) and comprises a transgene encoding sequences for FOXP3 and ThPOK, wherein the two coding sequences are in-frame and are separated by an in-frame coding sequence for a self-cleaving peptide (claims 19-20, 25-26), and an IRES immediately upstream of the transgene (claim 21). As FOXP3 and ThPOK are both lineage commitment factors that promote the differentiation of the iPSCs to CD4+ Tregs, this therefore renders obvious the method of instant claim 17.
Regarding claim 22: Following the discussion of claim 21, Conway et al further disclose that the heterologous sequence further comprises, immediately upstream of the IRES, a nucleotide sequence comprising all the exonic sequences of the T cell specific gene locus that are downstream of the integration site, such that the T cell specific gene locus remains able to express an intact T cell specific gene product (Paragraphs [0010], [0019]). This therefore reads on the method of the instant claim.
Regarding claim 29: Following the discussion of claim 1, Conway et al further disclose that the engineered cells further comprise a suicide gene (Paragraphs [0015], [0049]-[0050], [0075]-[0077]). As the engineered cells can comprise CD4+CD8+ T cells (Paragraphs [0025], [0028], [0087], [00108]), this therefore renders obvious the method of the instant claim for the same reasons as discussed in the rejection of claim 17.
Regarding claims 36 and 39: Following the discussion of claim 35, Conway et al further disclose that the genetically engineered Treg cells can be used in cell therapy and administered to a subject suffering from an autoimmune disease (claim 39) (Paragraphs [0016], [0037], [0091]-[0093]). This therefore renders obvious the method of instant claim 36 for the same reasons as discussed in the rejection of claim 35.
Conclusion
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/ALYSSA G WESTON/Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633