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 .
Claim Status
Claims 1-3, 13-16, 18-28, and 34 were previously pending.
Applicant’s election without traverse of the invention of group I (claims 1-3, and 24) and the species of “thymidine phosphorylase wherein the ubiquitination site on the thymidine phosphorylase is inhibited by thymidine or a derivative or analogue of thymidine” in the reply filed on 23 May, 2025 were previously acknowledged. Applicant previously amended claims 16, 18-21, and 23 to read on the elected invention. Therefore, the restriction requirement with regard to claims 16, 18-21, and 23 was withdrawn and the claims were rejoined with claims 1-3, and 24.
Claims 13-15, 22, 23, 25-28, and 34 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim.
Receipt is acknowledged of the claim amendments filed 13 October, 2025. Claims 1, 3, 16, 18-21, and 23 are amended. Claims 2, 13-15, 22, 25-28, and 34 are canceled. Claims 36-46 are newly added.
Newly added claims 40-46 do not read on the elected species of target protein wherein the target protein is “thymidine phosphorylase wherein the ubiquitination site on the thymidine phosphorylase is inhibited by thymidine or a derivative or analogue of thymidine”, which was elected in the reply filed 23 May, 2025 and which was treated as an election without traverse in view of MPEP § 818.01(a) in the Non-Final Rejection dated 11 July, 2025. Claim 40 reads on two alternative target proteins, one lacking a ubiquitination site entirely and one which comprises a modification that prevents ubiquitination. The former embodiment was already withdrawn from consideration as being drawn to a non-elected invention in copending claim 23. The latter does not read on the elected species because a thymidine phosphorylase with a modification that prevents ubiquitination is not able to also have ubiquitination inhibited by thymidine. Accordingly, new claims 40-46 are withdrawn from consideration as being drawn to a non-elected species.
Therefore, claims 1, 3, 16, 18-21, 24, and 36-39 are pending and are the subject of the present Official Action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/EP2020/076335, filed 21 September, 2020, which claims priority to United Kingdom of Great Britain And Northern Ireland Application No. GB1913592.0, filed 20 September, 2019. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copies of papers required by 37 CFR 1.55 have been filed in this application on 15 March, 2022.
The earliest possible priority for the instant application is 20 September, 2019.
Drawings
The drawings filed on 15 March, 2022 are accepted by the Examiner.
Withdrawn Objections/Rejections in view of Applicant’s Amendments/Arguments
Specification
The objection to the specification for lacking a descriptive title is withdrawn in view of Applicant’s amendments. Applicant has amended the title to more clearly describe the invention in the application.
Claim objection
The objection to claims 2, 3, 16, 17, 18, 19, 20, 21, 23 is withdrawn in view of Applicant’s amendments to the claims. Applicant has amended the claims to use the appropriate articles.
Claim Rejections - 35 USC § 112
The rejection of claims 1-3, 16, 18-21, and 24 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 is withdrawn in view of Applicant’s amendments to the claims.
Claim Rejections - 35 USC § 101
The rejection of claims 1-3, 16, 18-21, and 24 under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon/natural product without significantly more is withdrawn in view of Applicant’s amendments to the claims. Applicant has amended the claims to require in vitro and to require an exogenous ubiquitination inhibitor or artificially elevated levels of a ubiquitination inhibitor.
Claim Rejections - 35 USC § 102
The rejection of claims 1-3, 16, 18-21, and 24 under 35 U.S.C. 102(a)(1) as being anticipated by WO 2018/009838 (Published: 11 January, 2018) (hereinafter “Harandi”) (of record) as evidenced by Meinders et al., (Molecular Therapy Methods & Clinical Development 17 (2020): 822-830, and O'Dwyer et al., Cancer research 47.15 (1987): 3911-3919; hereinafter “O’Dwyer”) is withdrawn in view of Applicant’s amendments to the claims.
Applicant has amended the claims to require an exogenous ubiquitination inhibitor or artificially elevated levels of a ubiquitination inhibitor in the in vitro method. Harandi does not teach these amended limitations.
Note that support for the recitation of “artificially elevated levels of a ubiquitination Inhibitor” as required in amended claim 1 is found in paragraph [0064] of the published application. (see also page 11 of Applicants’ remarks).
Regarding claim 1, Harandi discloses a method of manufacturing a population of reticulocytes comprising providing a population of erythroid precursor cells (CD34+ cells), and culturing the erythroid precursor cells to differentiate them into reticulocytes (Harandi, page 12). The erythroid precursor cells and reticulocytes necessarily express thymidine phosphorylase as evidenced by Meinders who teaches that CD34+ cells inherently express thymidine phosphorylase (TP) (Meinders, Figure. 1). Ubiquitination of TP is necessarily hindered or prevented by Thymidine as evidenced by Meinders who teaches that TP’s substrate binding site is a ubiquitination site and that said ubiquitination sites are only exposed (able to be ubiquitinated) in the absence of substrate (thymidine) (Meinders, Abstract). Further, the erythroid precursor cells and reticulocytes necessarily possess thymidine as evidenced by O’Dwyer who teaches that thymidine is a naturally occurring nucleoside that is necessarily present in mitotically active cells (O’Dwyer, “Introduction”).
However, Harandi does not teach an exogenous ubiquitination inhibitor or artificially elevated levels of a ubiquitination inhibitor as recited in amended claim 1.
New Rejections Necessitated by Applicant’s Amendments to the claims
Claim Rejections - 35 USC § 103
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, 3, 16, 18-21, 24, and 36-39 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/009838 (Published: 11 January, 2018) (hereinafter “Harandi”) (of record) as evidenced by Meinders et al., (Molecular Therapy Methods & Clinical Development 17 (2020): 822-830, and in view of Koury et al., Annu. Rev. Nutr. 24.1 (2004): 105-131. (hereinafter “Koury”).
Regarding claim 1, Harandi discloses a method of manufacturing a population of enucleated erythroid cells in vitro comprising providing a population of erythroid precursor cells (CD34+ cells), and culturing the erythroid precursor cells to differentiate them into enucleated erythroid cells (Harandi, page 12; page 24, first paragraph). The erythroid precursor cells and enucleated erythroid cells necessarily express thymidine phosphorylase as evidenced by Meinders who teaches that CD34+ cells inherently express thymidine phosphorylase (TP) (Meinders, Figure. 1). Ubiquitination of TP is necessarily hindered or prevented by Thymidine as evidenced by Meinders who teaches that TP’s substrate binding site is a ubiquitination site and that said ubiquitination sites are only exposed (able to be ubiquitinated) in the absence of substrate (thymidine), wherein “supplementation of culture media with thymidine during differentiation reduces enzyme degradation, doubling the amount of TP retained in reticulocytes” (Meinders, Abstract). Meinders also evidences that endogenous thymidine is inherently present in CD34+ stem cells (page 822; col 2, fist para).
Harandi does not disclose an exogenous ubiquitination inhibitor or artificially elevated levels of a ubiquitination inhibitor in the method.
Koury teaches to add exogenous thymidine at 20μmol/L to an in vitro culture of erythroid cells from folate-deficient donors to rescue the erythroid cells from an apoptotic fate (Koury, page 113, first partial paragraph). Thus, a person having ordinary skill in the art would have understood from Koury that, at least where erythroid cells are isolated from a folate deficient donor, thymidine should be added to in vitro culture of erythroid cells to prevent apoptosis.
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have artificially elevated the levels of thymidine as taught by Koury in the method of producing reticulocytes in vitro of Harandi and to have arrived at the invention claimed in instant claim 1 with a reasonable expectation of success because at least where the erythroid cells of Harandi are sourced from folate-deficient donors, they would have been motivated to add thymidine to the culture to prevent apoptosis. Further, since erythroid precursor cells and reticulocytes necessarily express thymidine phosphorylase whose ubiquitination site is necessarily inhibited by thymidine as evidenced by post filing art of Meinders, a person having ordinary skill in the art would understand that an inherent property of supplementation of thymidine would be that it prevents ubiquitination of thymidine phosphorylase and results in elevated levels of thymidine phosphorylase.
Regarding claim 3, Harandi discloses differentiating CD34+ cells into reticulocytes and erythrocytes (Harandi, page 25).
Regarding claim 16, the combined teachings of Harandi as evidenced by Meinders and Koury render obvious claim 1, where TP is an endogenous protein as evidenced by Meinders.
Regarding claims 18 and 36, the combined teachings of Harandi as evidenced by Meinders and Koury render obvious claim 1, where the CD34+ cells of Harandi necessarily express TP and necessarily comprise Thymidine which is both a natural substrate and an inhibitor of ubiquitination for TP as evidenced by Meinders. Further, Koury teaches to supplement in vitro cultures of erythroid cells with thymidine.
Regarding claims 19-21, thymidine phosphorylase is an enzyme and is necessarily expressed by the CD34+ cells of Harandi as evidenced by Meinders.
Regarding claim 24, the reticulocyte produced by the method of Harandi is an erythroid cell.
Regarding claims 37-39, the combined teachings of Harandi as evidenced by Meinders and Koury render obvious claim 1. Moreover, Koury teaches to add thymidine to the in vitro culture of erythroid cells to prevent apoptosis when those erythroid cells are sourced from folate-deficient donors. It is noted that, "where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A). Further, in In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because "obvious to try" is not a valid rationale for an obviousness finding. Where a variable is recognized as result-effective (as is the case with thymidine in Koury), a person having ordinary skill in the art would have been motivated to determine the optimum or workable ranges of said variable by routine experimentation. In this case, a person having ordinary skill in the art would have been motivated to determine the optimal timing of addition of thymidine in the method of Harandi and Koury by routine experimentation because Koury teaches that thymidine addition to the culture of erythroid cells from folate-deficient donors is result-effective.
Response to Arguments
Applicant argues (1) against the application of Meinders as prior art and argues (2) Harandi does not teach any of the new limitations in amended claim 1(c). These arguments have been fully considered but are not found to be persuasive for the following reasons.
(1) Applicant argues “the cited Meinders paper is not available as prior art. The instant application is a 35 U.S.C. 371 national stage filing of PCT/EP2020/076335 (filed September 21, 2020), which claims priority to GB1913592.0 (filed September 20, 2019). Therefore, the instant application has an effective filing date of September 20, 2019. The Meinders paper was published June 2020, after the effective filing date (9/20/2019) of the instant application, and as such, is not available as prior art under 35 U.S.C. § 102(a)(1)” Remarks at 13.
This argument has been fully considered but has not been found persuasive because Meinders is relied upon for showing an inherent property of the erythroid cells in the method of Harandi. In certain circumstances, references cited to show a universal fact need not be available as prior art before applicant’s filing date. In re Wilson , 311 F.2d 266, 135 USPQ 442 (CCPA
1962). Such facts include the characteristics and properties of a material or a scientific
truism. In this case, the rejection does not hinge on Meinders but it is provided to show that the erythroid cells of Harandi necessarily possess thymidine phosphorylase as an inherent property of the cells. Thus, Meinders does not need to be available as prior art and this argument is not found to be persuasive.
(2) Applicant also argues “Harandi does not teach or would have suggested step c), wherein the erythroid progenitor is cultured in the presence of an exogenous ubiquitination inhibitor or artificially elevated levels of a ubiquitination inhibitor during at least a portion of the maturation process.” Remarks at 14.
This argument has been fully considered but has not been found persuasive because Harandi is no longer being used in an anticipation rejection and is now being applied along with Koury in an obviousness rejection as necessitated by Applicant’s amendment to the claims. Koury teaches to add thymidine to the in vitro culture of erythroid cells to prevent apoptosis when those erythroid cells are sourced from folate-deficient donors. A person having ordinary skill in the art would have been motivated to determine the optimal timing of addition of thymidine in the method of Harandi and Koury by routine experimentation because Koury teaches that thymidine addition to the culture of erythroid cells from folate-deficient donors is result-effective. Therefore, this argument has been fully considered but has not been found persuasive.
Conclusion
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 nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRENDAN THOMAS TINSLEY whose telephone number is (703)756-5906. The examiner can normally be reached Mon-Fri 8:00-5:00.
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/BRENDAN THOMAS TINSLEY/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634