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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 08 December 2025 has been entered.
Status of the Claims
Applicant’s submission filed 08 December 2025 has been entered. Claims 1-20 are pending. Claims 1, 3, and 12 have been amended. Therefore, prosecution on the merits continues for claims 1-20. All arguments have been fully considered with the status of each prior ground of rejection set forth below.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 1-4 and 6 under 35 USC 103 over Fong et al as evidenced by Giai et al
Applicant's arguments filed 08 December 2025 have been fully considered but they are not persuasive.
Applicant has traversed the rejection, asserting in Pages 4-5 of the Remarks filed 08 December
2025 that Fong et al as evidenced by Giai et al fail to teach an ex vivo expanded cell population that is at least 80% GMPs without the use of isolation techniques since the disclosure of Fong et al is instead directed to mixed population culturing. In response, the Examiner respectfully submits that Fong et al disclose that the ex vivo expanded cell population starts with a portion of GMPs (Paragraphs [0013], [0017]-[0018], [0022]-[0023], [0055]). The Examiner notes that the claims do not require that the ex vivo population of cells to be purely GMPs, as indicated by the newly added limitation defining the percentage of GMPs within the ex vivo expanded and unisolated cell population. Furthermore, the Examiner respectfully submits that Fong et al disclose that the ex vivo expanded cultures comprise expanded GMPs in which the GMP cell population is expanded at least about 80 fold and is at least about 50% of the total cells in culture (Paragraph [0023]). Therefore, the ordinary artisan would recognize from the disclosure of Fong et al that the expansion of the heterogenous population of cells can be routinely optimized such that the GMPs are at least 80% of the final cell population, as it is not outside the skillset of the ordinary artisan to tailor the culturing conditions such that GMPs predominantly proliferate (Fong et al: Paragraphs [0018]-[0023]; Figures 1-2). See MPEP § 2144.05(II).
Applicant has further traversed the rejection, asserting in Page 5 of the Remarks filed 08 December 2025 that since the disclosure of Fong et al is limited to the mixed population culturing, which results in heterogenous and further differentiated cell population, the ordinary artisan would not appreciate that the claimed, highly homogenous GMP cell population for use in the disease treatment of an inflammatory condition or infection can be obtained using a method disclosed in Fong et al. In response, the Examiner respectfully submits that the features upon which Applicant relies (i.e., culturing a homogenous population of GMPs) are not recited in the rejected claims. Although the claims are interpreted in light of the Specification, limitations from the Specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Therefore, the rejection is maintained and modified to encompass the claims as written.
RE: Rejection of claims 1- 6 under 35 USC 103 over Fong et al as evidenced by Giai et al in view of Rao et al
Applicant's arguments filed 08 December 2025 have been fully considered but they are not persuasive.
Applicant has traversed the rejection, citing the same assertions presented within Pages 4-5 of the Remarks filed 08 December 2025 in regards to the rejection over Fong et al as evidenced by Giai et al. In response, the Examiner respectfully directs Applicant to the discussion of 35 USC 103 rejection over Fong et al as evidenced by Giai et al.
Therefore, the rejection is maintained and modified to encompass the claims as written.
RE: Rejection of claims 1-4, 6-7, and 9-10 under 35 USC 103 over Fong et al as evidenced by Giai et al in view of Nguyen et al
Applicant's arguments filed 08 December 2025 have been fully considered but they are not persuasive.
Applicant has traversed the rejection, asserting in Pages 7-8 of the Remarks filed 08 December 2025 that Nguyen et al fail to disclose an ex vivo expanded cell population wherein at least 80% of the cell population is GMPs, wherein the ex vivo expanded GMP cell population has a uniform morphology of being round-shaped and non-adherent. In response, the Examiner respectfully submits that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Nguyen et al was a secondary reference relied upon to teach the genetic modification of the GMPs comprising a knockout – or disruption – of a gene encoding SIRPα or PI3Kγ via gene editing systems.
Therefore, the rejection is maintained and modified to encompass the claims as written.
RE: Rejection of claims 1-4, 6, and 8 under 35 USC 103 over Fong et al as evidenced by Giai et al in view of Gill et al
Applicant's arguments filed 08 December 2025 have been fully considered but they are not persuasive.
Applicant has traversed the rejection, asserting in Pages 8-9 of the Remarks filed 08 December 2025 that Gill et al fail to disclose an ex vivo expanded cell population wherein at least 80% of the cell population is GMPs, wherein the ex vivo expanded GMP cell population has a uniform morphology of being round-shaped and non-adherent. In response, the Examiner respectfully submits that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Gill et al was a secondary reference relied upon to teach the genetic modification of the GMPs such that they comprise a vector of DNA fragment encoding a chimeric antigen receptor.
Therefore, the rejection is maintained and modified to encompass the claims as written.
RE: Rejection of claims 1-4, 6, 11-18, and 20 under 35 USC 103 over Fong et al as evidenced by Giai et al in view of Hanna et al as evidenced by ThermoFisher Scientific
Applicant's arguments filed 08 December 2025 have been fully considered but they are not persuasive.
Applicant has traversed the rejection, asserting in Pages 9-10 of the Remarks filed 08 December 2025 that the ordinary artisan would not have had a reasonable expectation of success in combining the methods described in Fong et al and Hanna et al to culture the GMPs in the culture medium as recited in the instant claims, as the disclosure of Hanna et al is instead focused on the culturing of pluripotent stem cells. In response, the Examiner respectfully submits that it is not required that the expectation of success be a certainty; only one that is reasonable to a person of ordinary skill. In re Longi, 759 F.2d 887, 897 (Fed. Cir. 1985) (“Only a reasonable expectation of success, not absolute predictability, is necessary for a conclusion of obviousness”). In the instant case, the ordinary artisan would have had a reasonable expectation of success since the additional factors allow for the expansion of hematopoietic stem cells – from which GMPs are derived from – wherein the cells remain substantially morphologically unchanged after undergoing multiple passages. Furthermore, Fong et al disclose that the starting population of cells comprises hematopoietic stem cells (Paragraph [0018]), so it would have therefore been prima facie obvious to include the hematopoietic stem cell culture factors of Hanna et al within the starting cell culture of Fong et al.
Applicant has further traversed the rejection, asserting in Page 10 of the Remarks filed 08 December 2025 that Hanna et al fail to disclose an ex vivo expanded cell population wherein at least 80% of the cell population is GMPs, wherein the ex vivo expanded GMP cell population has a uniform morphology of being round-shaped and non-adherent. In response, the Examiner respectfully submits that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Hanna et al was a secondary reference relied upon to teach the incorporation of a B-Raf kinase inhibitor and a Wnt activator and/or GSK-3 inhibitor into the culture medium.
Therefore, the rejection is maintained and modified to encompass the claims as written.
RE: Rejection of claims 1-4, 6, and 11-20 under 35 USC 103 over Fong et al as evidenced by Giai et al, in view of Hanna et al as evidenced by ThermoFisher Scientific, and further in view of Thomson et al
Applicant's arguments filed 08 December 2025 have been fully considered but they are not persuasive.
Applicant has traversed the rejection, asserting in Page 11 of the Remarks filed 08 December 2025 that the ordinary artisan would not have had a reasonable expectation of success in culturing the GMPs as instantly claimed when considering the disclosures of Fong et al, Hanna et al, and Thomson et al, as Thomson et al discloses the culturing of hematopoietic progenitor cells which are distinct from GMPs. In response, the Examiner respectfully submits that the ordinary artisan would have been able to predictably substitute the GSK-3 inhibitor with the Wnt activator SKL2001 since both function to promote Wnt signaling within cell culture. See MPEP § 2143(I)(B).
Applicant has further traversed the rejection, asserting in Page 14 of the Remarks filed 08 December 2025 that Thomson et al fail to disclose an ex vivo expanded cell population wherein at least 80% of the cell population is GMPs, wherein the ex vivo expanded GMP cell population has a uniform morphology of being round-shaped and non-adherent. In response, the Examiner respectfully submits that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Thomson et al was a tertiary reference relied upon to teach the incorporation of a Wnt activator into the culture medium.
Therefore, the rejection is maintained and modified to encompass the claims as written.
RE: Rejection of claims 1-20 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-15, and 20-22 of US Patent No. 12,006,513 B2 in view of Fong et al, Rao et al, and Gill et al
Applicant has requested in Page 12 of the Remarks filed 08 December 2025 that the double
patenting rejection be held in abeyance until the claims of this case be deemed allowable otherwise. In response, Applicant is reminded that 37 CFR 1.111 requires that replies by applicant or patent owner must reply to every ground of objection and rejection in the prior Office action. Only objections or requirements as to form not necessary to further consideration of the claims may be requested to be held in abeyance until allowable subject matter is indicated. Non-statutory double patenting rejections may not be held in abeyance. See MPEP § 714.02. The Examiner would like to note that Applicant did not traverse the non-statutory double patenting rejection.
Therefore, the rejection is maintained and modified to encompass the claims as written.
New/Maintained Grounds of Rejection
Claim Rejections - 35 USC § 112
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 1-20 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. The claims contain 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Independent claim 1 is directed to a method for treating an inflammatory condition or infection in a subject in need thereof comprising transplanting an effective amount of an ex vivo expanded cell population of granulocyte/macrophage progenitor cells (GMPs) to the subject, wherein at least 80% of the ex vivo expanded and unisolated cell population is GMPs and wherein the ex vivo expanded GMPs have a uniform morphology of being round-shaped and non-adherent. A review of the Specification shows that Applicant has failed to provide support for an “unisolated cell population”. More specifically, Applicant has failed to articulate – and it is not readily apparent to the Examiner – where within the instant disclosure an ex vivo expanded population of cells comprising at least 80% GMPs without the use of any isolation techniques has been described. Therefore, the subject matter of claim 1 can be considered an addition of new matter. See MPEP § 608.04(a), Waldemar Link, GmbH & Co. v. Osteonics Corp., 32 F.3d 556, 559, 31 USPQ2d 1855, 1857 (Fed. Cir. 1994); Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1560, 19 USPQ2d 1111, 1114 (Fed. Cir. 1991) (A written-description question often arises when an applicant, after filing a patent application, subsequently adds "new matter" not present in the original application.); In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981).
Instant claims 2-20 are included because they depend from a rejected claim.
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 1-20 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 1: Independent claim 1 recites the limitation "the… unisolated cell population" in Line 4. There is insufficient antecedent basis for this limitation in the claim, as there is no prior recitation of an unisolated cell population within the claim, and the ex vivo expanded population being unisolated is not necessarily an inherent feature of the ex vivo expanded population. See MPEP § 2173.05(e).
Instant claims 2-20 depend upon independent claim 1 and thus inherit the deficiencies of the independent claim, thereby rendering them indefinite as well.
Appropriate correction is required.
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 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 1-4 and 6 remain rejected under 35 U.S.C. 103 as being unpatentable over Fong et al (US 2014/0377234 A1, of record) as evidenced by Giai et al (Blood, 2013, of record).
Fong et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2).
Regarding claims 1-3: Fong et al disclose methods of expanding myeloid progenitor cells, and utilizing the expanded cell population in therapeutic treatments for neutropenia and/or bacterial infections arising in patients subjected to myeloablative therapy and hematopoietic stem cell transplantation (Abstract; Paragraphs [0012], [0026]-[0028], [0055], [0148], [0157]-[0165], [0171]-[0172]).
As such, Fong et al disclose that the expanded myeloid progenitor cells are ex vivo expanded granulocyte/macrophage progenitors (GMPs) (Paragraphs [0014], [0022], [0055], [0072], [0092], [0099], [0113]-[0114], [0133], [0138], [0148], [0153], [0163]).
Fong et al further disclose that the ex vivo expanded progenitor cells maintain their progenitor potential, are non-adherent, and have a rounded shape (Paragraphs [0142], [0232], [0307], [0315]-[0316]; Figure 2A). It is also of note that GMPs are inherently non-adherent and round-shaped – as evidenced both by Page 1 and Figure 1 of Giai et al, as well as Figure 1A of the instant Specification.
Fong et al further disclose that the final ex vivo expanded culture preparation comprises a GMP population which has been expanded at least about 80 fold and is at least about 50% of the total cells in culture (Paragraph [0023]). Fong et al further disclose that the GMPs are cultured in chemically defined medium allowing for the proliferation of the GMPs (Paragraphs [0018]-[0023], [0062], [0068]-[0069], [0072]-[0073]).
Fong et al further disclose that the expanded GMPs are transplanted into the patient concurrently or subsequent to stem cell transplantation (Paragraphs [0160], [0166]-[0176]).
However, Fong et al do not exemplify or reduce to practice a method of treating an inflammatory condition or infection wherein at least 80% of the ex vivo expanded and unisolated population is GMPs, as required by instant claim 1.
Therefore, it would have been prima facie obvious to have modified the expansion and treatment method of Fong et al such that at least 80% of the final ex vivo expanded and unisolated culture preparation is GMPs, as Fong et al teach that at least about 50% of the total cells in the ex vivo expanded culture are GMPs, and it would not have been outside the skillset of the ordinary artisan to tailor the culturing conditions such that GMPs predominantly proliferate (Paragraphs [0018]-[0023]; Figures 1-2). See MPEP § 2144.05(II). It also would have been prima facie obvious to administer a substantially pure population of GMPs – comprising at least 80% GMPs – because Fong et al disclose a cell population having a significant proportion of GMPs, as compared to CMPs and MEPs, will provide amelioration of neutropenia (Paragraph [0133]). Furthermore, one of ordinary skill in the art before the effective filing date of the invention would have had a reasonable expectation of success given that Fong et al suggest substantially pure populations GMPs can be generated, and populations with high concentrations provide therapy to specific inflammatory diseases, such as neutropenia. See MPEP § 2143(I)(G).
Consequently, Fong et al disclose the treatment of neutropenia (claim 2) or a bacterial infection (claim 3) within a subject in need thereof, wherein an effective amount of an ex vivo expanded and unisolated cell population comprising at least 80% granulocyte/myeloid progenitors (GMPs) are administered to the subject. As the GMPs are inherently non-adherent and round-shaped – as evidenced both by Page 1 and Figure 1 of Giai et al, as well as Figure 1A of the instant Specification – this therefore renders obvious the method of instant claim 1. See MPEP § 2112.
Regarding claim 4: Following the discussion of claim 1, Fong et al further disclose that an antifungal agent, an antibacterial agent, an antiviral agent, platelets, cytokines, and/or growth factors are also administered to the subject (Paragraphs [0160], [0166]-[0176]). As these are immunologic agents, this therefore reads on the method of the instant claim.
Regarding claim 6: Following the discussion of claim 1, Fong et al further disclose that the GMPs are allogeneic to the subject (Paragraphs [0102], [0146]-[0148], [0154], [0163]). This therefore reads on the method of the instant claim.
Claims 1-6 remain rejected under 35 U.S.C. 103 as being unpatentable over Fong et al (US 2014/0377234 A1, of record) as evidenced by Giai et al (Blood, 2013, of record), in view of Rao et al (International Journal of Infectious Diseases, 2017, of record).
The discussion of Fong et al as evidenced by Giai et al in regards to claim 1 can be observed
above and is relied upon herein, the content of which is incorporated in its entirety. Fong et al as evidenced by Giai et al render obvious claims 1-4 and 6. Rao et al is considered prior art under 35 USC 102(a)(1).
Regarding claim 5: Following the discussion of claim 4 above, Fong et al disclose that an antibacterial agent is also administered to the subject suffering from a bacterial infection (Paragraphs [0160], [0166]-[0176]).
Fong et al do not disclose that the antibacterial agent is an anti-PD-1/PD-L1 antibody, as required by instant claim 5.
Rao et al, however, disclose anti-PD-1/PD-L1 therapy for the treatment of infectious diseases, including tuberculosis (Page 225, Infectious diseases).
Therefore, it would have been prima facie obvious to have modified the bacterial infection treatment method of Fong et al such that the antibacterial agent is an anti-PD-1/PD-L1 antibody, as detailed in Rao et al. One of ordinary skill before the effective filing date of the invention would have been motivated to combine two therapeutics that are known to treat bacterial infections, and would have had a reasonable expectation of success based on Fong et al’s disclosure of this combination therapy of GMPs and an antibacterial agent. See MPEP § 2143(I)(G).
Consequently, Fong et al as evidenced by Giai et al and as modified by Rao et al render obvious a method of treating a subject suffering from a bacterial infection, wherein GMPs and an anti-PD-1/PD-L1 antibody are administered to the subject. This therefore renders obvious the method of the instant claim.
Claims 1-4, 6-7, and 9-10 remain rejected under 35 U.S.C. 103 as being unpatentable over Fong et al (US 2014/0377234 A1, of record) as evidenced by Giai et al (Blood, 2013, of record), in view of Nguyen et al (US 2019/0076473 A1, of record).
The discussion of Fong et al as evidenced by Giai et al in regards to claim 1 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Fong et al as evidenced by Giai et al render obvious claims 1-4 and 6. Nguyen et al is considered prior art under 35 USC 102(a)(2), with an effective filing date of 14 September 2017.
Regarding claims 7 and 9-10: As aforementioned in the discussion of claim 1 above, Fong et al disclose the treatment of a subject in need thereof, wherein an effective amount of ex vivo expanded granulocyte/myeloid progenitors (GMPs) are administered to the subject.
Fong et al do not disclose the genetic modification of the GMPs comprising a knockout – or disruption – of a gene encoding SIRPα or PI3Kγ via gene editing systems, as required by instant claims 7 and 9-10.
Nguyen et al, however, disclose the deletion of the gene encoding SIRPα in macrophages derived from granulocyte/macrophage progenitors using gene editing systems, such as transcription activator-like effector nucleases (TALEN) or zinc finer nucleases (ZFN) (Paragraphs [0048], [0054], [0075]-[0086], [0110]-[0111], [0114], [0118]-[0121]).
Therefore, it would have been prima facie obvious to mimic the SIRPα deletion detailed in Nguyen et al within the GMPs of Fong et al utilizing the well-known genetic knockout techniques. One of ordinary skill in the art before the effective filing date of the invention would have recognized that the SIRPα inhibition within macrophages is translatable to GMPs, as the GMPs predictably differentiate into macrophages (Nguyen et al: Paragraphs [0075]-[0086]). Accordingly, the ordinary artisan would have had predictable results since the GMPs and macrophages are functionally comparable. See MPEP § 2143(D).
Consequently, Fong et al as evidenced by Giai et al and as modified by Nguyen et al render obvious a method of administering GMPs to a subject in need thereof, wherein the GMPs are genetically modified using either a TALEN or ZFN gene editing system (claim 9) to have a knockout (claim 10) of the gene encoding SIRPα (claim 7). This therefore renders obvious the method of the instant claims.
Claims 1-4, 6, and 8 remain rejected under 35 U.S.C. 103 as being unpatentable over Fong et al (US 2014/0377234 A1, of record) as evidenced by Giai et al (Blood, 2013, of record), in view of Gill et al (US 2018/0244748 A1, of record).
The discussion of Fong et al as evidenced by Giai et al in regards to claim 1 can be observed
above and is relied upon herein, the content of which is incorporated in its entirety. Fong et al as evidenced by Giai et al render obvious claims 1-4 and 6. Gill et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2).
Regarding claim 8: As aforementioned in the discussion of claim 1 above, Fong et al disclose the treatment of a subject in need thereof, wherein an effective amount of ex vivo expanded and unisolated granulocyte/myeloid progenitors (GMPs) are administered to the subject.
Fong et al do not disclose the genetic modification of the GMPs such that they comprise a vector or DNA fragment encoding a chimeric antigen receptor (CAR), as required by instant claim 8.
Gill et al, however, disclose the genetic modification of ex vivo expanded macrophages such that they comprise a vector encoding a CAR (Paragraphs [0013], [0159], [0161], [0206], [0210]-[0212], [0241], [0252], [0294]). Gill et al further disclose that the macrophages can be derived from progenitors (Paragraphs [0277], [0285]).
Therefore, it would have been prima facie obvious to mimic the CAR expression detailed in Gill et al within the GMPs of Fong et al utilizing the well-known transduction techniques (Gill et al: Paragraphs [0241]-[0251], [0253]). One of ordinary skill in the art before the effective filing date of the invention would have recognized that the CAR expression within macrophages is translatable to GMPs, as the GMPs predictably differentiate into macrophages (Fong et al: Paragraphs [0055], [0063], [0072]). Accordingly, the ordinary artisan would have had predictable results since the GMPs and macrophages are functionally comparable. See MPEP § 2143(D).
Consequently, Fong et al as evidenced by Giai et al and as modified by Gill et al render obvious a method of administering GMPs to a subject in need thereof, wherein the GMPs are genetically modified to comprise a vector encoding a CAR. This therefore renders obvious the method of the instant claim.
Claims 1-4, 6, 11-18, and 20 remain rejected under 35 U.S.C. 103 as being unpatentable over Fong et al (US 2014/0377234 A1, of record) as evidenced by Giai et al (Blood, 2013, of record), in view of Hanna et al (US 2017/0275593 A1, of record) as evidenced by ThermoFisher Scientific (Technical Resources: B-27 Serum-Free Supplement, 2023, of record).
The discussion of Fong et al as evidenced by Giai et al in regards to claim 1 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Fong et al as evidenced by Giai et al render obvious claims 1-4 and 6. Hanna et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2).
Regarding claim 11: Following the discussion of claim 1, Fong et al further disclose a method of expanding an ex vivo population of granulocyte/macrophage progenitors (GMPs) by culturing the cells in a medium comprising a mixture of cytokines and growth factors that promote growth and expansion of the GMPs (Abstract; Paragraphs [0018]-[0023], [0092], [0099]-[0100], [0113]-[0145]).
Fong et al do not disclose the culturing of the GMPs in a medium that further comprises a B-Raf kinase inhibitor and a Wnt activator and/or GSK-3 inhibitor, as required by instant claim 11.
Hanna et al, however, disclose culture mediums comprising growth factors, a B-Raf kinase inhibitor, and GSK-3 inhibitor that are capable of morphologically maintaining stem cells undergoing multiple cell passages or clonal expansion (Paragraphs [0016], [0022], [0540]).
Therefore, it would have been prima facie obvious to modify the expansion method of Fong et al to include culture medium that comprises growth factors, a B-Raf kinase inhibitor, and GSK-3 inhibitor as detailed in Hanna et al, since the additional factors allow for the expansion of stem cells – from which GMPs are derived from – wherein the cells remain substantially morphologically unchanged after undergoing multiple passages. One of ordinary skill before the effective filing date of the invention would have been reasonably motivated to utilize the same culture medium for the derived GMPs thereof, as doing so would enable the prolonged maintenance of GMPs and thereby minimize the associated time and labor required for culture upkeep. There would also be a reasonable expectation of success with predictable results based on the disclosure and resulting cell conditions of Hanna et al (Paragraphs [1128]-[1133]; Figure 14, Conditions 81-83). See MPEP § 2143(I)(G).
Consequently, Fong et al as evidenced by Giai et al and as modified by Hanna et al render obvious a method of administering GMPs to a subject in need thereof, wherein the GMPs are ex vivo expanded in a culture medium comprising a growth factor, a B-Raf kinase inhibitor, and GSK3-inhibitor. This therefore renders obvious the method of the instant claim.
Regarding claims 12-14: Following the discussion of claim 11, Hanna et al further disclose that the base culture medium is a 1:1 mix of Neurobasal Medium and DMEM/F12 (Paragraph [1043]). This therefore renders obvious the method of the instant claims for the same reasons as discussed in the rejection of instant claim 11 above.
Regarding claims 15-16: Following the discussion of claim 11, Hanna et al further disclose that the base culture medium also comprises insulin, apo-transferrin, bovine serum albumin fraction V, putrescine, and sodium selenite, as well as being supplemented with B27 (claim 15) (Paragraph [1043]). As the B27 supplement also comprises human recombinant insulin, human transferrin, BSA fraction V, putrescine 2HCl, sodium selenite, DL α-tocopherol, and linolenic acid itself, this therefore renders obvious the method of instant claim 16 for the same reasons as discussed in the rejection of instant claim 11 above. See ThermoFisher Scientific B-27 Technical Resource.
Regarding claim 17: Following the discussion of claim 11, Hanna et al further disclose that the growth factor comprised within the cell culture medium may be stem cell factor (Paragraphs [0022]-[0025]). This therefore renders obvious the method of the instant claims for the same reasons as discussed in the rejection of instant claim 11 above.
Regarding claim 18: Following the discussion of claim 11, Hanna et al further disclose that the B-Raf kinase inhibitor comprised within cell culture medium may be SB590885 (Paragraphs [0385]-[0386]). This therefore renders obvious the method of the instant claims for the same reasons as discussed in the rejection of instant claim 11 above.
Regarding claim 20: Following the discussion of claim 11, Hanna et al further disclose that the GSK-3 inhibitor comprised within cell culture medium may be CHIR99021 (Paragraphs [0329]-[0331]). This therefore renders obvious the method of the instant claims for the same reasons as discussed in the rejection of instant claim 11 above.
Claims 1-4, 6, and 11-20 remain rejected under 35 U.S.C. 103 as being unpatentable over Fong et al (US 2014/0377234 A1, of record) as evidenced by Giai et al (Blood, 2013, of record), in view of Hanna et al (US 2017/0275593 A1, of record) as evidenced by ThermoFisher Scientific (Technical Resources: B-27 Serum-Free Supplement, 2023, of record), and further in view of Thomson et al (US 2020/0080059 A1, of record).
The discussion of Fong et al as evidenced by Giai et al in regards to claim 1 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. In addition, the discussion of Fong et al as evidenced by Giai et al, and in view of Hanna et al in regards to claim 11 can be observed above and is relied upon herein, the content of which is also incorporated in its entirety. Fong et al as evidenced by Giai et al render obvious claims 1-4 and 6. Fong et al as evidenced by Giai et al, and in view of Hanna et al as evidenced by ThermoFisher Scientific render obvious claims 1-4, 6, 11-18, and 20. Thomson et al is considered prior art under 35 USC 102(a)(2), with an effective filing date of 07 September 2018.
Regarding claim 19: As aforementioned in the discussion of claim 11 above, Fong et al as evidenced by Giai et al and as modified by Hanna et al render obvious a method of treating a subject in need thereof comprising the administration of GMPs to the subject, wherein the GMPs are ex vivo expanded within a culture medium comprising a growth factor, a B-Raf kinase inhibitor, and GSK3-inhibitor.
Hanna et al further discloses that the GSK-3 inhibitor is included to promote Wnt signaling (Paragraph [0008]).
Fong et al as evidenced by Giai et al in combination with Hanna et al do not teach the inclusion of a Wnt activator selected from the list of SKL 2001, BML-284, WAY 262611, CAS 853220-52-7, and/or QS11 within the culture medium, as required by instant claim 19.
Thomson et al, however, disclose methods for generating and using hematopoietic progenitor cells (Abstract).
As such, Thomson et al disclose that Wnt/β-catenin signaling pathway activation is achieved by contacting the cells with an agent that disrupts the interaction of β-catenin with Axin, a member of the β-catenin destruction complex. Disruption of the Axin-β-catenin interaction allows β-catenin to escape degradation though the destruction complex thereby increasing the net level of β-catenin to drive β-catenin signaling. Accordingly, Thomson et al discloses in one embodiment of the invention that the Axin-β-catenin interaction can be disrupted in hematopoietic progenitor cells by contacting them with the compound 5-(Furan-2-yl)-N-(3-(1H-imidazol-1-yl)propyl)-1,2-oxazole-3-carboxamide (“SKL2001”). Likewise, in another embodiment, the activator of Wnt/β-catenin signaling is a GSK-3 inhibitor, such as CHIR99021 (Paragraph [0051]).
Therefore, it would have been prima facie obvious to have substituted the GSK-3 inhibitor within the culture medium from the combined method of Fong et al and Hanna et al with the Wnt activator SKL2001 from Thomson et al, as doing so would be a simple substitution of one known factor for another. See MPEP § 2143(I)(B). One of ordinary skill before the effective filing date of the invention would have recognized that the two factors are functionally comparable (Thomson et al: Paragraph [0051]), as both function to promote Wnt signaling, and thus would have been able to substitute the factors with predictable results.
Consequently, Fong et al as evidenced by Giai et al and as modified by Hanna et al and Thomson et al render obvious the method of treating a subject in need thereof comprising administering GMPs to the subject, wherein the GMPs are ex vivo expanded in a culture medium comprising a growth factor, B-Raf kinase inhibitor, and Wnt activator – specifically SKL2001. This modified method therefore renders obvious the method of the instant claim.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-20 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-15, and 20-22 of U.S. Patent No. 12,006,513 B2 in view of Fong et al (US 2014/0377234 A1, of record on the IDS filed 09 May 2024), Rao et al (International Journal of Infectious Diseases, 2017, of record), and Gill et al (US 2018/0244748 A1, of record). The instant application is a CONTINUATION of US Patent No. 12,006,513 B2.
Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims render obvious the instant claims. More specifically, the patented claims are not identical because no single patented claim discloses all of the limitations of any of the instant claims; however, each of the limitations of the instant claims are disclosed by separate patented claims, or rendered obvious by the accompanying prior art. The fact that each of the elements were claimed in the patent application, just not in a single claim, still renders obvious the instant invention because each of the features, though separately claimed, can be physically combined into a single embodiment.
Patent claim 1 is directed to a method for the expansion of a population of granulocyte/macrophage progenitor cells (GMPs), comprising:
culturing GMPs in a culture medium comprising:
(i) a growth factor,
(ii) a B-Raf kinase inhibitor, and
(iii) a Wnt activator and/or a GSK-3 inhibitor,
wherein the GMPs remain substantially morphologically unchanged after undergoing multiple cell passages and/or clonal expansion.
Patent claim 1 does not disclose a method for treating an inflammatory condition or infection in a subject in need thereof, wherein an effective amount of the ex vivo expanded and unisolated cell population comprising at least 80% GMPs is administered to the subject.
Fong et al, however, disclose the treatment of neutropenia or a bacterial infection within a subject in need thereof, wherein an effective amount of ex vivo expanded GMPs are administered to the subject.
Fong et al further disclose that the final ex vivo expanded and unisolated culture preparation comprises a GMP population which is at least about 50% of the total cells in culture (Paragraph [0023]).
It therefore would have been prima facie obvious to have modified the method of patent claim 1 to utilize the expanded GMPs within a treatment method, as a person of ordinary skill in the art before the effective filing date of the invention would have been motivated to treat subjects in need thereof with the therapeutic GMPs. It also therefore would have been prima facie obvious to have modified the method of patent claim 1 such that at least 80% of the final ex vivo expanded and unisolated culture preparation is GMPs, as Fong et al reasonably suggest and/or render obvious the ex vivo expansion of unisolated GMPs to provide a substantially pure sample of GMPs – or a sample comprising at least 80% GMPs. As the GMPs are inherently non-adherent and round-shaped, this therefore renders obvious the method of instant claims 1-3 and 11.
With that, each of patent claims 7-15 are exactly or substantially identical to each of instant claims 12-20, respectively. Likewise, patent claims 20-22 read on instant claims 7 and 9-10.
Furthermore, although the patent does not disclose the limitations from instant claims 4-6 and 8, the subject matter is known from the prior art and can be further incorporated into the method rendered obvious by patent claim 1 and Fong et al:
Fong et al teach the limitations in instant claims 4 and 6.
Rao et al teach the limitation in instant claim 5.
Gill et al teach the limitation in instant claim 8.
Conclusion
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/ALYSSA G WESTON/Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633