VBNadfsxz DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 22 May, 2026 has been entered.
Claims 1, 3, 16, 18-21, 23-24 and 36-46 were previously pending.
Receipt is acknowledged of the claim amendments filed 22 May, 2026. Claim 1 is amended. Claim 47 is newly added.
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.
Claims 40-46 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. In addition, claim 23 as written depends from withdrawn claim 40. Therefore, claim 23 is also withdrawn from further consideration.
Therefore, claims 1, 3, 16, 18-21, 24, 36-39, and 47 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 was previously 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.
Claim Objections
Claim 1 is objected to because of the following informalities: abbreviations/acronyms need to be spelled out upon their first encounter in the claims (for example: “BEL-A”). Appropriate correction is required.
Claim 23 is objected to because of the following informalities: Claim 23 depends from a later-presented claim 40. Dependent claims should refer back to a previously presented claim. Therefore, claim 23 should be cancelled and the limitations therein moved to a dependent claim or a new claim which occurs after withdrawn claim 40. Appropriate correction is required.
Withdrawn Objections/Rejections in view of Applicant’s Amendments/Arguments
Claim Rejections - 35 USC § 103
The rejection of claims 1, 3, 16, 18-21, 24, and 36-39 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”) is withdrawn in view of Applicant’s amendments and arguments.
Applicant has amended claim 1 to require BEL-A derived cells. Harandi and Koury are silent with regard to BEL-A cells. In addition, Applicant has argued that “neither Koury nor Harandi provides or suggests providing any ubiquitination inhibitor to result in elevated levels of a target protein or polypeptide in an enucleated erythroid cell” (Remarks, page 9). This argument is found persuasive because, while Koury teaches to add thymidine to a culture of erythroid cells, there is no teaching of the effect on thymidine phosphorylase of this supplementation. Accordingly, this rejection is withdrawn.
New Rejections
Claim Rejections - 35 USC § 102
Claim 24 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Persons, et al. Nature medicine 4.10 (1998): 1201-1205, hereinafter “Persons”.
It is noted that "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted). See MPEP 2113. Here, the product is an erythroid cell with elevated levels of any protein. Persons teaches red blood cells (RBCs) modified to express green fluorescent protein (GFP) (Persons, Table 1, Fig. 2). Since RBCs do not naturally express GFP, the GFP expression of persons is “elevated”. Therefore, Persons teaches erythroid cells (RBCs) with elevated levels of a target protein (GFP), and anticipates the invention claimed in instant claim 24.
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 1, 3, 16, 18-21, 24, and 36-39 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.
Amended claim 1 recites “BEL-A derived erythroid progenitor” in the third line of the claim. This recitation is unclear because it is unclear what steps are required by the claim in order to derive the erythroid progenitor cells of the present invention. It is unclear whether Applicant intends the claim to encompass a first step of differentiating erythroid progenitor cells from BEL-A cells or whether Applicant intends some other construction where the cells could be considered “derived” but where they were never actually differentiated from BEL-A cells. Accordingly, a person having ordinary skill in the art would not be apprised of the scope of the patent protection sought. Claims 3, 16, 18-21, 24, and 36-39 are further rejected for their dependency on a rejected base claim.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 16 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 16 depends from claim 1 and attempts to limit any target protein or any polypeptide to either exogenous or endogenous proteins or polypeptides but these attempted limitations do not further limit claim 1 because the terms “exogenous” and “endogenous” are operational definitions which, taken together, describe all possible proteins since every protein is either produced from within the cell (endogenous) or introduced from the outside (exogenous). Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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, 3, 16, 18-21, 24, 37-39, and 47 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 inventors, at the time the application was filed, had possession of the claimed invention.
The claims broadly encompass a vast genus of methods for making erythroid cells comprising elevated levels of a target protein or polypeptide wherein the cells express any target protein or any polypeptide and the cells are cultured in the presence of any amount of any exogenous ubiquitination inhibitor or any artificially elevated levels of any ubiquitination inhibitor “in an amount sufficient to result in elevated levels of the target protein or polypeptide”. There is not sufficient structure recited in the claims for performing the recited function of elevating levels of the target protein or polypeptide. In addition, in reading on any target protein or polypeptide and any ubiquitination inhibitor, the claims broadly encompass a vast genus encompassing virtually any protein or polypeptide (even those which themselves do not possess canonical ubiquitination sites but which may be downregulated by another protein which does), and virtually any agent which downregulates or blocks any component of the ubiquitin-mediated proteasomal degradation pathway. Claim 16 limits any target protein or any polypeptide to either exogenous or endogenous proteins or polypeptides but these limitations do not further limit the breadth of the claims because the terms “exogenous” and “endogenous” are operational definitions which, taken together, describe all possible proteins since every protein is either produced from within the cell (endogenous) or introduced from the outside (exogenous) (See 35 U.S.C. 112(d) rejection below). Claim 18 limits the ubiquitination inhibitor to one which is a natural substrate or natural product of the target protein or polypeptide or one which is a reversible inhibitor of a natural substrate or natural product of the target protein or polypeptide. Thus, claim 18 establishes a relationship between the target protein or polypeptide and the ubiquitination inhibitor selected. However, this language is still broad in that it captures proteins and polypeptides that have yet to be discovered whose ubiquitination sites happen to lay within their substrate binding sites or whose ubiquitination sites are exposed upon substrate binding. Claim 20 limits the target protein to being one enzyme from a list of 15 distinct enzymes but continues to read on any ubiquitination inhibitor which when cultured with the cells has the functional property of producing “elevated levels of the target protein or polypeptide”. Claim 21 is the first claim which specifies a specific target protein (thymidine phosphorylase) and a specific ubiquitination inhibitor (one of thymidine, deoxyuridine, thymine, uridine, 2-deoxy ribose I-phosphate). However, claim 21 also recites “derivatives or analogues thereof” encompassing a vast genus of potential ubiquitination inhibitors derived from one of those listed or designed or discovered to be analogues to one of those listed. Claim 36 is the only claim which specifies that the target protein is thymidine phosphorylase and that the ubiquitination inhibitor is thymidine. The remainder of the pending claims specify timing of ubiquitination inhibitor addition to the culture.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021). Further, A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus."). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). See MPEP 2163(II)(A)(3)(a)(ii).
The working examples presented by Applicant in the supporting disclosure provide only a single example wherein erythroid progenitor cells were cultured in the presence of 5mM thymidine at different points in the culture process to result in increased thymidine phosphorylase in reticulocytes produced through the method (Specification, Example 5). Applicant argued in their remarks that “the Examiner has not demonstrated that providing 20 μmol/L thymidine, or any other ubiquitination inhibitor, is ‘an amount sufficient to result in elevated levels of the target protein or polypeptide’ as recited in the currently amended claims” (Remarks, page 9). It is noted that this argument rests on the assertion that 20μmol/L thymidine would not be enough to result in elevated levels of the target protein and, as acknowledged by Applicant, “addition of thymidine can arrest cell cycle and also inhibited cell growth in K562 cells at a concentration of 1mM” (Specification, page 23, lines 7-8). Thus the precise concentration of thymidine appears to be a necessary component of the instant invention as too little will result in not obtaining the functional property claimed while too much will kill the cells. Working example 5 only shows 5mM as a sufficient dose of thymidine to result in the functional properties claimed for thymidine phosphorylase specifically. In addition, the precise timing of thymidine addition is important to the functioning of the method as there was an increase in cell death and inhibition of differentiation when thymidine was added at day 0 of differentiation (Specification, Example 5). With regard to any other target proteins or any other ubiquitination inhibitors, the working examples teach that four other enzymes (glutamine synthase, adenosine deaminase, L-asparaginase, and uricase) could be expressed in erythroid progenitor cells and that those cells could be differentiated into reticulocytes with an ultimate reduction in the level of the four enzymes over time (Specification, Example 6; FIG. 8-11). The specification continues “To explore whether ubiquitination enhances [glutamine synthase] enzyme retention at the end of culture, MG132 (a ubiquitination inhibitor) was added at day 15 to the [glutamine synthase] (over)expressing erythroblasts. Expression was measured at day 19 by flow cytometry.” (Specification, Example 6). However, Applicant has provided no characterization of the effects of MG132 that resulted from this measurement. There is no description of the amount of MG132 used, nor the examination of its effects on the expression of any of these enzymes at all. In the final example, Applicant searched for ubiquitin consensus sequences on “key enzymes” (Specification, Example 7). However, no evaluation of a ubiquitination inhibitor at all was performed on any of these other identified “key enzymes”. The only description Applicant has provided for a method for making erythroid cells comprising elevated levels of a target protein or polypeptide wherein the cells express any target protein or any polypeptide and the cells are cultured in the presence of any amount of any exogenous ubiquitination inhibitor or any artificially elevated levels of any ubiquitination inhibitor “in an amount sufficient to result in elevated levels of the target protein or polypeptide” is the specific description of the culture of erythroid progenitor cells in the presence of 5mM thymidine to result in elevated levels of thymidine phosphorylase. Any attempt to claim other species within the genus claimed, let alone the entire genus, amounts to a command to the skilled artisan to identify other such target proteins and other such precise amounts of particular ubiquitination inhibitors to practice the instant invention.
The art at the time of filing generally taught not to add a general ubiquitination inhibitor, to a culture of erythroblasts where enucleation of those erythroblasts is sought (See Chen et al. Experimental hematology 30.7 (2002): 634-639, Abstract). Chen teaches that two proteosome inhibitors, lactacystin and MG132 have dose-dependent effects on enucleation and that 1μM of each independently decreased enucleation to less than 40% of controls while 2.5μM produced apoptotic-like morphologies in the cells (Chen, page 636, Results). Chen acknowledged that there was no complete blockage of enucleation, but cautioned that further research is needed to determine the compensatory mechanisms at play which allow some enucleation to occur in the presence of MG132 and lactacystin (Chen, page 638, second and third full paragraphs). Thus, the skilled artisan at the time of filing knew from Chen that general ubiquitination inhibitors which act on the proteosome like MG132 and lactacystin have an inhibitory effect on the enucleation of erythroid progenitor cells and that the precise dosage of the inhibitor determines how significant of an inhibitory effect is seen with higher doses producing an apoptotic fate. In addition, the art at the time of filing teaches methods of differentiating erythroid progenitor cells into reticulocytes and that said cells naturally possess thymidine phosphorylase (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, hereinafter “Meinders” (of record)). 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). While the art does teach to add 20μM thymidine to a culture of erythroid cells, there is no teaching of the effect on thymidine phosphorylase of this supplementation (See Koury et al., Annu. Rev. Nutr. 24.1 (2004): 105-131. (hereinafter “Koury”) (of record)). In addition, as acknowledged by Applicant, “addition of thymidine can arrest cell cycle and also inhibited cell growth in K562 cells at a concentration of 1mM” citing to Anisimov et al. and Thomas et al. (Specification, page 23, lines 7-8). Thus, even with respect to the particular target protein/ubiquitination inhibitor claimed and exemplified by Applicant, the skilled artisan at the time of filing knew that the precise concentration thymidine is necessary to be able to produce erythrocytes with elevated levels of thymidine phosphorylase because 1mM kills progenitor cells and inhibits differentiation into erythrocytes.
Accordingly, Applicant has not disclosed a representative number of species sufficient to demonstrate to the skilled artisan in the field of in vitro erythrocyte culture that Applicant had possession of the claimed invention. Applicant has only described 5mM thymidine added to a culture of erythroid progenitors to result in elevated levels of thymidine phosphorylase.
Conclusion
No claim is allowed. However, claims 1, 3, 16, 18-21, 36-39, and 47 are indicated as free of the prior art of record because the prior art of record does not teach, suggest, or motivate a person having ordinary skill in the art to differentiate erythroid progenitor cells in the presence of a ubiquitination inhibitor. While the art does teach in vitro methods of differentiating erythroid progenitor cells (See Harandi), and the addition of 20μM thymidine to a culture of erythroid progenitor cells (See Koury), the art does not teach any peptides or proteins whose expression is elevated by the 20μM thymidine. In addition, the art generally teaches not to add MG132, a general ubiquitination inhibitor, to a culture of erythroblasts where enucleation of those erythroblasts is sought (See Chen et al. Experimental hematology 30.7 (2002): 634-639, Abstract).
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 MARVICH/Primary Examiner, Art Unit 1634
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