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 .
Election/Restrictions
Applicant's election with traverse of Group I, claims 70-84 in the reply filed on 08/21/2025 is acknowledged. The traversal is on the ground(s) that Group II is drawn to the product made by the method of Group I and Group II is drawn to a kit comprising the elements necessary to carry out the method of Group I. This is not found persuasive because the cells of Invention II can be made by a different method and the claims of Group II read on a product of nature because the construct in the engineered iPSC is not required to be maintained. The kit of Group III has other uses that are distinct from the elected method of differnetiating iPSCs into CD7+ NK/T progenitors. Searching Group I does not require a search of the limitations of Group III. The requirement is still deemed proper and is therefore made FINAL.
Claims 85-89 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 08/21/2025.
Claim Objections
Claim 1 is objected to because of the following informalities: Claim 1 has two separate steps labeled as step (d). The second step (d) is considered as step (e) that is referenced in dependent claims 79 and 84. Appropriate correction is required.
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 70-84 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the claimed method wherein the culturing the population of cells in the presence of a Notch ligand for between 9 and 17 days comprises co-culturing the population of differentiating cells in the presence of a stromal cell feeder layer, does not reasonably provide enablement for carrying out this step without stromal cells. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
The nature of the invention relates to increasing efficiency of directing differentiation of pPSCs to become CD7+ T/NK progenitors by early/premature induction of Notch signaling along with a culture protocol that guides pPSCs to become CD7+ T/NK progenitors. The invention further matures the progenitors into either T or NK cells by co-culture with different densities of OP9 stromal cells that secrete a Notch ligand.
The claims are drawn to generation of T/NK progenitors and recites a step of culturing the cells in the presence of a Notch ligand for between 9 and 17 days.
Oh (2019, Mol. Cells, 42:200-209, IDS), for example, reviews the directed differentiation of pluripotent stem cells and supports that a variety of cell types, including neurons, pancreatic b-cells, can be reliably obtained including neurons, pancreatic-cells, skeletal and cardiac muscle and hepatocytes by varying culture conditions and forced expression of different sets of genes. Ebrahimi (2020, Stem Cell Research and Therapy, 11:483, pages 1-13, IDS) reviews the directed differentiation of pluripotent stem cells into erythroid cells and teaches,
“This developmental procedure is controlled by cell-cell/cell-matrix interactions along with several cytokines and growth factors including IL-3, IL-6, erythropoietin (EPO) (the main erythropoietic stimulating hormone), EPO-receptor, members of the transforming growth factor-β (TGF-β), activin A, activin receptor-II, Flt3 ligand (Flt3-L), vascular endothelial growth factor (VEGF), stem cell factor (SCF), thrombopoietin (TPO), and granulocyte colony-stimulating factor (G-CSF)” (Ebrahimi, 2).
With regard to cardiac differentiation, Fujita (2019, Stem Cells, 37:992-1002; IDS) states, “complex genetic and epigenetic circuits coordinately regulate cardiac differentiation and maturation from hPSCs “(see page 992). Gene expression is not the only factor in controlling differentiation as Podkalicka (2020, Biomolecules, 10:1614, pages 1-30; IDS) teaches the importance of oxygen levels in differentiation as early embryogenesis occurs in relatively hypoxic conditions (see page 3 and Section 5.1, page 10).
The specification teaches directing differentiation of pluripotent stem cells to a population of cells comprising a specific CD7+ T/NK progenitor cells. This involves tight regulation of gene expression and culture conditions including media components and oxygen levels. The specification refers to this culture process as an iT protocol. This protocol is diagrammed as follows:
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Herrerra (frontiers in immunology, 2017,8:755, pages 1-10) compared stromal cell layers for the differentiation of NK cells and found OP9 to be superior and that M2-10B4 provides good support for cells in long-term culture and OP9 is superior to M2-10B4 cells for the generation of NK cells, exemplifying the importance of the stromal cells in this process. Roth (J Mol Med (2007) 85:1047–1056) teaches that stromal cells secrete factors and carry cell surface proteins that are important in NK cell differentiation. The in vivo environment for NK/T cell differentiation comprises stromal cells. Stromal cells provide many signals, not just the notch ligand (see Abel, 2018, Front Immunol., 9:1869, pages 1-23). Addition of notch ligand to the environment created by stromal cells, can lead to T cell development, as supported by the Specification. However, there is nothing of record to support that Notch ligand alone will lead cells to become CD7+ NK/T precursors without the presence of stromal cells. See also Miller (1994, Blood, 83:9,1-8).
Thus, it would have required undue experimentation to carry out the method as claimed without the presence of stromal cells.
Applicant’s Remarks have been fully considered but are not persuasive. Applicant points to paragraphs 15,109,105 and 11 for support for carrying out the claimed method in the presence of a Notch ligand without the presence of stromal cells. This support is descriptive support and is not enabling, as set forth above. The working Examples carry out the claimed method only in the presence of stromal cells. The state of the art (above) supports that stromal cells provide numerous factors to the culture environment that affects differentiation, not just Notch ligand. Stromal cells provide many signals, not just the notch ligand (see Abel, 2018, Front Immunol., 9:1869, pages 1-23). Addition of notch ligand to the environment created by stromal cells, can lead to T cell development, as supported by the Specification. However, there is nothing of record to support that Notch ligand alone will lead cells to become CD7+ NK/T precursors without the presence of stromal cells.
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.
The rejection of claims 70,72-79,82-84 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-9 and 13-15 of U.S. Patent No. 11,788,065 is withdrawn in light of the incorporation of the limitation of claim 71 into claim 70. Substitution of the Notch ligand for stromal cells would not have predictably led to the claimed cell population. An obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical but an examined application is not patentably distinct from the reference claims because the examined claim is either anticipate by, or would have been obvious over, the reference claims. See, e.e., 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). Although the conflicting claims are not identical, they are not patentably distinct from each other because claim 1 is generic to all that is recited in claim 1 of US 11,788,065. That is, claim 1 of ‘065 falls entirely within the scope of claim 1 of the instant application. Specifically, claim 1 of ‘065 is identical to the instant claim 1 with the exception that claim 1 of ‘065 is limited to a stromal cell layer as the source of the Notch ligand but has all of the elements recited in the instant rejected claims. Dependent claims 72-79 and 82-84 are the same limitations as patented dependent claims 2-9 and 13-15.
Conclusion
THIS ACTION IS MADE FINAL. 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.
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VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632