DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claims 1-14 are under consideration in this office action.
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 1-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 12,024,722. Although the claims at issue are not identical, they are not patentably distinct from each other because the patent claims are an anticipatory species of the instant claims.
Regarding claim 1, patent claim 1 discloses (i) providing a first cell, (ii) introducing a reprogramming factor selected from essentially the same listed species of gene regulators as instant claim 1, (iii) placing the cell in hematopoietic cell medium; and (iv) maintaining in the medium until hematopoietic multipotent cells are generated. The instant claim specify hematopoietic stem cells (HSC), which is a subset of the cells found in hematopoietic multipotent cells. Given the gene regulatory fectors/reprogramming factors are the same, one would reasonable expect that that the HSC to be present in the multipotent cell population of the patent claim. As such, patent claim 1 is an anticipatory species of instant claim 1.
Regarding claim 2, patent claim 2 discloses many of the same SEQ ID NOS. as instant claim 2.
Regarding claim 3, patent claim 1 does not disclose that the HSC express one or more markers of CD34, Flt3, Sca-1, HoxB4 and CXCR4. However, these are known markers of HSCs. Since the method of patent claim 1 are reasonably expected to produce HSC, one of ordinary skill would also expect that the HSC express art accepted markers thereof.
Regarding claim 4, patent claim 3 has identical claim language to instant claim 4. As such, it is an obvious species variant of instant claim 4 for reasons discussed above.
Regarding claim 5, patent claim 4 has identical claim language to instant claim 5. As such, it is an obvious species variant of instant claim 5 for reasons discussed above.
Regarding claim 6, patent claim 5 has identical claim language to instant claim 6. As such, it is an obvious species variant of instant claim 6 for reasons discussed above.
Regarding claim 7, patent claim 1 discloses the subpopulation of reprogramming/gene regulatory elements claimed. As such, patent claim 1 discloses obvious species variant of instant claim 7 for reasons discussed above.
Regarding claim 8, patent claim 2 discloses a subset of the claimed regulatory genes claimed. Further, for the SEQ ID NOS not disclosed by the patent claims, these SEQ ID NOS are prior art established sequences for the claimed factors and thus obvious variants.
Regarding claim 9, patent claim 1 discloses “introduction” thus increase of “agent(s) selected from the group consisting of”. The term “agent(s)” means “at least one agent” or “one or more agents” which encompasses “at least two” as claimed.
Regarding claim 10, patent claim 6 (i) providing a first cell type; (ii) contacting chromatin and/or DNA of the cell with identical chromatin remodeling/reprogramming agents; (iii) transiently introducing the same polynucleotides encoding reprogramming/gene regulatory agents as claimed. The patent claims recite hematopoietic multipotent cells which are expected to included HSC as discussed above. As such, patent claim 6 recites an anticipatory species variant of claim 10.
Regarding claim 11, patent claim 7 discloses the some of same SEQ ID NOS.
Regarding claim 12, patent claim 8 discloses the same claim language as claim 12.
Regarding claim 13, patent claim 9 discloses the same claim language as recited in claim 13.
Regarding claim 14, patent claims 1 and 6 disclose a species of this claim as discussed above.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994)
The disclosure of the prior-filed applications, Application Nos. 13/464,987, 13/504,988, PCT/CA2010/001727, 61/256,967, fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. While these prior-filed applications in general terms contemplate transforming a first cell type to a HSC, the disclosures in these applications fail to provide specific, enabling guidance to specific reprogramming agents that will predictably transform a cell of the first type into an HSC. As discussed in the scope of enablement rejection, not all reprogramming agents will predictably results in the transformation of a first cell type to HSC and the disclosures of these prior filed applications do not teach which reprogramming agents will predictable result in HSC production from a first cell type. As such, the claims are denied the benefit of these prior-filed applications earlier filing date and the effective filing date for the instant claims is 3/15/2013.
Claim Rejections - 35 USC § 102/103
The following is a quotation of the appropriate paragraphs of pre-AIA 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claim(s) 1, 3, 6, 7, 9, and 14 is/are rejected under pre-AIA 35 U.S.C. 102 (b) as anticipated by or, in the alternative, under pre-AIA 35 U.S.C. 103(a) as obvious over Wang (Wang et al. PNAS 102(52):19081-19086, 2005).
Regarding claim 14, Wang discloses transiently inducing Cdx4 expressing in murine embryonic stem cells (ESCs) present in an embryoid body (EB) to promote hematopoietic lineage differentiation (abstract; p. 19081, col 2, Cell Culture paragraph under Methods; Fig. 1; p. 19083, col 1, 1st paragraph under Results). These disclosures by Wang expressly disclose transiently increasing expression of at least one gene regulator, wherein said expression of the at least one regulator is necessary for existence of HSC as recited in step (i). Wang further discloses that Cdx4 expression also promoted HOXB4 and GATA1 expression in said differentiating cells derived from said ESC (abstract; Fig 2; p.19083, col 1 and two section starting “Cdx4 promotes both…” ). These disclosures expressly discloses stably expressing said at least one gene regulator, as recited in step (ii). Wang further discloses we demonstrate that ectopic Cdx4 expression promotes hematopoietic mesoderm specification, increases hematopoietic progenitor formation, and, together with HoxB4, enhances multilineage hematopoietic engraftment of lethally irradiated adult mice. Clonal analysis of retroviral integration sites confirms a common stem cell origin of lymphoid and myeloid populations in engrafted primary and secondary mice. These data document the cardinal stem cell features of selfrenewal and multilineage differentiation of ESC-derived hematopoietic stem cells (abstract; p. 19084, col 1, staring “Cdx4 enables engraftment…” to p. 19086, col 2 end of result section; Table 1). These disclosures expressly disclose the limitations of step (iii).
Regarding claim 1, Wang discloses providing murine ESCs in an EB and transiently inducing Cdx4 expressing in the murine ESCs present in EB to promote hematopoietic lineage differentiation (abstract; p. 19081, col 2, Cell Culture paragraph under Methods; Fig. 1; p. 19083, col 1, 1st paragraph under Results). Cdx4 expression as described increased Hox4B and GATA1 expression in said cells within the EB (abstract; Fig 2; p.19083, col 1 and two section starting “Cdx4 promotes both…” ). These disclosure expressly disclose (i) providing a cell of a first type and (ii) transiently increasing in said cell of a first of a first type at least gene regulator selected from the group consisting of GATA1. Wang further discloses we demonstrate that ectopic Cdx4 expression promotes hematopoietic mesoderm specification, increases hematopoietic progenitor formation, and, together with HoxB4, enhances multilineage hematopoietic engraftment of lethally irradiated adult mice. Clonal analysis of retroviral integration sites confirms a common stem cell origin of lymphoid and myeloid populations in engrafted primary and secondary mice. These data document the cardinal stem cell features of selfrenewal and multilineage differentiation of ESC-derived hematopoietic stem cells (abstract; p. 19084, col 1, staring “Cdx4 enables engraftment…” to p. 19086, col 2 end of result section; Table 1). These disclosures expressly disclose (iii) placing a cell in a cell culture medium and maintaining intracellular levels of gene regulator for a sufficient period of time to allow stable expression endogenous expression of at least one gene regulator and (iv) maintaining the cell in cell culture medium for a sufficient period of time to allow stable expression of a plurality of secondary genes whose expression is characteristic of phenotypical and/or functional properties of HSC, wherein at least one of the said secondary genes is not characteristic of phenotypical and functional properties of an embryonic stem cell, whereby at the end of said period of time the cell of the first type has been transformed into a HSC.
Wang does not expressly state that the cell culture medium of steps (iii) and (iv) is a hematopoietic cell culture mediums. However, the claim does not specify any particular structural elements of the hematopoietic cell culture medium. Therefore the breadth of the “hematopoietic cell culture medium” encompasses any medium that is capable of “maintaining intracellular levels of gene regulator for a sufficient period of time to allow stable expression endogenous expression of at least one gene regulator” as recited in step (iii) and able to “allow stable expression of a plurality of secondary genes whose expression is characteristic of phenotypical and/or functional properties of HSC, wherein at least one of the said secondary genes is not characteristic of phenotypical and functional properties of an embryonic stem cell” as recited in step (iv). Clearly the medium of Wang is able to exact these functional properties. As such, Wang implicitly discloses the hematopoietic cell medium as claimed.
Regarding claim 3, Wang discloses expressing CD34, sca1, HoxB4, and other HSC markers (Table 2). Wang is silent as to the expression of Flt-3 and CXCR4. However, Wang provides ample functional evidence via engraftment do demonstrate the cells of Want are in fact HSC, thus it inherently would to express the relevant markers necessary to function as an HSC, including Flt-3 and CXCR4.
Regarding claim 6, Wang expressly discloses embryonic stem cells and derivatives thereof as claimed.
Regarding claim 7, Wang expressly discloses transiently increases HOXB4 and GATA1 as discussed above.
Regarding claim 9, Wang expressly discloses wherein intracellular levels of GATA1 and HOXB4 (i.e. expression of at least two gene regulators) are transiently increased as claimed.
In conclusion, the prior art of Want anticipates the claims because it expressly or inherently discloses all of the required limitations of the claims.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of pre-AIA 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(e) the invention was described in (1) an application for patent, published under section 122(b), by another filed in the United States before the invention by the applicant for patent or (2) a patent granted on an application for patent by another filed in the United States before the invention by the applicant for patent, except that an international application filed under the treaty defined in section 351(a) shall have the effects for purposes of this subsection of an application filed in the United States only if the international application designated the United States and was published under Article 21(2) of such treaty in the English language.
Claim(s) 14 is/are rejected under pre-AIA 35 U.S.C. 102(e) as being anticipated by Lemischka (US 2015/0004145 effective filing date:1/30/2012; of record in IDS 9/7/2018).
Regarding claim 14, Lemischka discloses a method of making HSC from differentiated cell by introducing a combination of transcription factors, wherein the combination comprises GATA2, GFI1B, and c-Fos (p. 2, [0012]). Lemischka discloses that these transcription factors are introduced and expressed in the differentiated cell by transfecting the differentiated cell with an excisable or inducible (Tet-off) lentiviral vector(s) encoding the combination of transcription factors (p. 19, Example 3, [0147] - [0152]). These disclosures encompass providing (i) transiently increasing in said cell of first type intracellular levels of at least one gene regulator necessary for the existence of HSC and (ii) stably expressing said at least one gene regulator. Lemischka discloses that the transient increase leads to the expression of CD31, CD34, CD38 lo/-, CD41, CD43, CD45, CD49f, Thy1/CD90, CD105, CD117/c-kit, CD133, CD150, Sca-1, Tie2, VE-Cadherin, KDR/FLK1, Flk-2/Flt3, and CXCR4 (p. 2, [0012]). Many of these markers are also known to affect or regulate other genes. These disclosures encompass stably expressing a plurality of secondary gene regulators, wherein said plurality of secondary gene regulators is the result of the stable expression of the at least one gene regulator, and herein (i) stable expression of said plurality of secondary genes is characteristic of phenotypical and functional properties of the HSC, (ii) stable expression of at least one of said secondary genes I not characteristic of phenotypical and functional properties of an embryonic stem cell, and wherein (i) and (ii) are indicative of successful reprogramming of the cell of the firs type to the HSC.
Thus Lemischka expressly discloses the limitations of claim 14.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of pre-AIA 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
Claim(s) 14 is/are rejected under pre-AIA 35 U.S.C. 102(b) as being anticipated by Estrov (US 2011/0206644 pub date:8/25/2011; of record in IDS 9/7/2018).
Regarding claim 14, Estrov discloses providing a normal human fibroblast (Example 7, p. 9, [0077]). Estrov discloses treating the fibroblast with a combination of 5-azacytidine and growth factors GM-CSF and SCF (i.e. limitations of (i)) for a sufficient amount of time to induce stable CD34 and CD45 expression (p. 9, [0077]-[0079]). These disclosures encompasses the limitations of steps ii-iii. Thus, Estrov discloses all of the limitations of claim 14.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 2, 4, 8, and 10-13 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Wang (Wang et al. PNAS 102(52):19081-19086, 2005) as applied to claim 1, 3, 6, 7, 9, and 14 above, and further in view of West (US2012/0129262 A1 effectively filed 10/22/2010) and Estrov (US 2011/0206644 pub date:8/25/2011).
Regarding claims 2, 8, and 11, Wang teaches that a murine ESC line with a tetracycline-inducible CDX4 expression vector was used in their method as discussed above. Wang does not teach that the tetracycline inducible vector comprises nucleic acid sequence/encodes a polypeptide sequence of the CDX4 sequence of SEQ ID NO:366/367. However, West teaches genetically modifying pluripotent cells to constitutively express or up or down-regulate a transcription factor or combination thereof to differentiation the pluripotent cells ([0091]). West teaches that the transcription factor can be a CDX4 having the sequence of Accession Number NM_005193.1, which has 100% sequence identity with SEQ ID NO:366 ([0094]) West teaches that the up or down regulator can be a tet- on/off inducible promoter system known in the art ([0094]).
As such, it would have been obvious to an artisan of ordinary skill at the time the invention was made that one could predictable use the teachings of the CDX4 tet inducible expression system taught by West in the method of making HSC taught by Wang to predictably arrive at the limitations of claims. An artisan would have a reasonable expectation of success because West teaches that tet inducible expression constructs and the sequences of SEQ ID NO:366/367 were well established in the art and being predictably used to differentiation embryonic stem cells and pluripotent stem cells. Thus, Wang in view of West render the limitations of claims 2, 8, and 11 obvious.
Regarding claims 4 and 10, Wang teaches the method of making HSC from a first cell type as above. Wang does not teach contacting the chromatin and/or DNA of the first cell type with an agent capable of recombining chromatin and/or DNA of said cell as claimed. However, Estrov teaches treating a cell to be reprogrammed to an HSC with a 5-azacytidine in addition to other reprogramming factors (p. 9, [0077]). Estrov teaches that said contacting for a sufficient amount of time induces CD34 and CD45 expression in the cells and transforms the cells into HSC (p. 9, [0077]-[0079]).
As such, it would have been obvious at the time the invention was made to combine contacting the cells comprising the introduced HSC reprogramming polypeptides, as taught by Wang, with a chromatin remodel agent, taught by Estrov, to predictably arrive at embodiments of the claims that combine introduction of specific HSC reprogramming factor into a first cell type with the treatment of the first cell type with a chromatin remodeling agent. An artisan of ordinary skill in the art would have a reasonable expectation of success because the method of both Wang and Estrov independently arrive at a transformed cell that has an HSC phenotype. As such, an artisan would minimally expect that the combination of the two methods would have at least the same outcome. Further, an artisan would be motivated to try the combination of the two methods because both predictably results in HSC and many examples in the prior art that demonstrate a synergistic effect when combining two induction method exist. Thus Wang in view of Estrov renders claims 4 and 10 obvious.
Regarding claim 12, Wang teaches the limitations of expression of one or more stem cell markers as claimed (i), no tumor growth (xi-xiii). Thus Wang in view of West and Estrov render the limitations of claim 12 obvious.
Regarding claim 13, Wang discloses that the HSC form colonies which are a three-dimensional structure (abstract, p.19082 and clonal analysis on p. 19085). Thus Wang in view of West and Estov render claim 13 obvious.
The combination of prior art cited above in all rejections under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A, B, and E are applicable. The claimed method was known in the art at the time of filing as indicated by Wang in view of West Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claim 5 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Wang (Wang et al. PNAS 102(52):19081-19086, 2005) as applied to claim 1, 3, 6, 7, 9, and 14 above, and further in view of Stice (US 2003/0217378 pub date:11/20/2003).
Wang teaches the claim as discussed above. Wang does not teach that the method further comprises treating the cell of a first type with a cytoskeleton disruptor. However, Stice teaches that cell being reprogrammed in nuclear transfer unit were commonly treated with the cytoskeleton disruptor, cytochalasin B to aid in the activation of the nuclear transfer unit and reprogramming process of the cell introduced into the nuclear transfer unit ([0117]-[0119]; [0123]; [0125]; [0164]; [0167]; claim 7).
As such, it would have been obvious to an artisan at the time the invention was made to include cytochalasin B, as taught by Stice, to the reprogramming method taught by Wang to arrive at the limitations of claim 5. An artisan would have a reasonable expectation of success and also would be motivated to include cytochalasin B in the reprogramming method because cytochalasin B has long been used in the process of reprogramming cells as it is seen used in nuclear reprogramming to aid in the activating and reprogramming process, as demonstrated by Stice.
The combination of prior art cited above in all rejections under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A and E-G are applicable. The claimed method was known in the art at the time of filing as indicated by Wang and Stice. Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
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 1-14 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 following:
A) An in vitro method of transforming a first cell type into a hematopoietic stem cell (HSC) comprising: (a) providing a cell of a first type; (b) introducing into the cell of a first type reprogramming agents, Brachyury (T), Caudal Type Homeobox 4 (CDX4), Homeobox B4 (HOXB4), GATA Binding Factor 1 (GATA1), Kruppel-like Factor 1 (KLF1), Left-right determination factor 1 (LEFTY1), Eomesodermin (EOMES), Delta-like protein 1 precursor (DLL1), GATA Binding factor 4 (GATA4), GATA binding factor 6 (GATA6), Heart and Neural Crest Derivatives Expressed -1 (HAND1), Insulin gene enhancer protein (ISL1) and NK2 Homeobox 5 (NKX2.5) or polynucleotides encoding said reprogramming agents; (c) culturing the cell of the first type of (b) in a HSC culture medium on laminin coated plates for a sufficient amount of time to transform the first cell type into an HSC (claim 1);
B) An in vitro method of transforming a first cell type into a HSC comprising: (i) providing a cell of a first type; ii) contacting chromatin and/or DNA of a cell of a first type with a histone acetylator, an inhibitor of histone deacetylation, a DNA demethylator, and/or an inhibitor of DNA methylation; iii) introducing into the cell of a first type of (ii) reprogramming agents, T, CDX4, HOXB4, GATA1, GATA2, KLF1, LEFTY1, EOMES, DLL1, GATA4, GATA6, HAND1, ISL1, and NKX2.5 or polynucleotides encoding said reprogramming agents; and iii) culturing the cell of a first type of (ii) for a sufficient amount of time to transform the first cell type into a HSC (claim 14); and
C) An in vitro method of reprogramming a cell of a first type to an HSC comprising: (a) introducing into the cell of a first type reprogramming agents, T, CDX4, HOXB4, GATA1, GATA2, KLF1, LEFTY1, EOMES, DLL1, GATA4, GATA6, HAND1, ISL1, and NKX2.5or polynucleotides encoding said reprogramming agents; (b) culturing the cell of the first type of (a) in a HSC culture medium on laminin coated plates for a sufficient amount of time to transform the first cell type into an HSC (claim 20);
does not reasonably provide enablement for the following:
1) An in vivo method of transforming a cell of a first type into a HSC;
2) A method of transforming a cell of a first cells type into a HSC that transiently increases in said cell of a first type intracellular levels of any reprogramming agent or agents, whereby said transient increase induced indirect or direct endogenous expression of at least one reprogramming factor; and
3) A method of transforming a cell of a first cells type into an HSC that transiently increases in said cell of a first type intracellular levels of reprogramming agent or agents by any means, whereby said transient increase induced indirect or direct endogenous expression of at least one reprogramming factor.
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 use the invention commensurate in scope with these claims.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention, if not, whether an artisan would require undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make and use the invention based on the content of the disclosure is “undue”.
1) Claims 10 and 14 are drawn to recites, a method of obtaining HSC comprising contacting a cell with a chromatin remodeling agent and increasing intracellular levels of at least one gene. The breadth of these methods encompasses both an in vivo and in vitro method.
The specification provide specific guidance to an in vitro culture method that introduces reprogramming factors a cell that induce an HSC phenotype in the cell. However, the specification fails to provide any guidance to an in vivo method of inducing a transformation or reprogramming of a cell to a desired cell of a second type, more particularly a HSC. Thus the specification fails to enable the breadth of the claims that encompass an in vivo method of transforming or reprogramming a first cell type to a second desired cells type, more particularly a HSC. Further, a search of the art at the time of the inventions fails to supplement the shortcomings of the specification because it also fails to provide specific guidance to a method of transforming or reprogramming a first cell type into a desired second cell type, more particularly a HSC.
As such, the breadth of the claims that encompass an in vivo method of transforming or reprogramming a first cell type into a desired second cell type, more particularly a HSC lacks enablement because the specification fails to provide specific, predictable guidance to such an in vivo method.
2) Claims 1, 10, and 14 and thus dependents, recites, “transiently increasing in said cell of a first type intracellular levels of at least one reprogramming agent, whereby said transient increase induces direct or indirect endogenous expression of at least one gene regulator". The breadth of these claims encompasses increasing intracellular levels of any one or more reprogramming factors or any gene regulator for that a cell in a cell to arrive a HSC.
The specification more narrowly teaches the following in example 34 (See Pre-Grant Publication):
[0460] Human adipocyte-derived stem cells (ADSC, Invitrogen) and HFF (ATCC, Cat. # CRL-2097) were transfected every other day for a total of three times with combinations of pCMV6-AC-CDX4, pCMV-AC-Gata1, pCMV-AC-Gata2, pCMV-XL5-HoxB4, pCMV-XL5-T, and pCMV-AC-KLF1 (all from Origene) and grown in hematopoietic stem cell medium (complete StemPro-43 medium, Invitrogen) on Lamini-411 (Biolamina) coated plates at 37.degree. C., 10% CO.sub.2, 5% O.sub.2 and supplemented with Stem Cell Factor (100 ng/ml, R&D Systems), IL-3 (50 ng/ml, R&D Systems), GM-CSF (25 ng/ml, R&D Systems), and human TPO (50 ng/ml, R&D Systems). After 2 weeks, the cells were transferred to a low-bind petri-dish (Corning) and grown in complete StemPro-43 medium supplemented with 3 U/ml erythropoietin, 50 ng/ml SCF, 20 ng/ml GM-SCF, 20 ng/ml IL-3, 20 ng/ml IL-6. Formed colonies were analyzed for the expression of CD34.sup.+ and Sca-1 indicating the presence of hematopoietic stem-like cells (HSLC).
As such, the specification more narrowly teaches one specific combination of reprogramming factors, more particularly, T, CDX4, HOXB4, GATA1, GATA2, and KLF1 that successfully resulted in HSC. The specification fails to describe any one reprogramming factor or any other combinations of reprogramming factors that transform a cell of the first cell type to an HSC. As such, the specification fails to enable any other one reprogramming agent or any other combinations of reprogramming factors, other than T, CDX4, HOXB4, GATA1, GATA2, and KLF1 to reprogram a cell into a HSC.
At the time of the invention, the art establishes that not all or any combination of reprogramming factors will predictably results in reprogramming a cell of a first type to a HSC as the claims and elected invention requires. For example, it is well established in the art, the combination of Oct-4, Sox-2, Klf-4, and c-Myc reprograms a differentiated cell type to a pluripotent state, not a HSC (Zhou et al. Cell Stem Cell 4:381-384, 2009; See page 381, cols 1-3; of record). As such, the art teaches that not all reprogramming factors or combinations thereof will predictably transform a cell of a first type to a HSC.
Thus, the breadth of the claims encompassing increasing intracellular levels of any one or more reprogramming agents in a cell of a first cell type to transform said cell of a first type into an HSC lacks enablement because the specification solely provides specific guidance to one combination of reprogramming agents, in particular T, CDX4, HOXB4, GATA1, GATA2, and KLF1, that successfully transform the cell to HSC and fails to provide specific guidance to any of the other possible reprogramming agents or combinations thereof embrace by the claims. Further, the art fails to supplement the shortcomings of the specification because the art teaches that not all reprogramming factors or a combination thereof will predictably produce HSC.
3) Claims 1, 10m and 14 recites, "transiently increasing in said cell of a first type intracellular levels of at least one gene regulator". The breadth of these recitations encompasses increasing intracellular levels of the any at least one gene regulator by any means. The breadth thus includes contacting a cell with a molecule that results in increased expression of an endogenous reprogramming factor. The breadth of the claims also encompasses some type of non-molecular stimulation of the cell that results in increased expression of an endogenous reprogramming factor as well. The breadth also encompasses introducing an exogenous reprogramming factor, such as a reprogramming peptide or a nucleic acid encoding a reprogramming agent.
However, as discussed above, the specification solely provides specific guidance to one means of increasing intracellular levels of a reprogramming agent and that is by introducing an exogenous combinations of reprogramming polypeptides or polynucleotides encoding said exogenous combinations of reprogramming polypeptides. The specification fails to provide specific guidance to any chemicals, drugs, or other molecules that can be contacted with the cell and predictably transform a first cell type into a second desired cell type. The specification also fails to provide specific guidance to any non-chemical or molecular stimuli that cause an increase in intracellular endogenous reprogramming factors. Thus, the specification fails to enable these embodiments or any other means of increasing intracellular levels of reprogramming factors, other than by introducing the reprogramming peptides or polynucleotides encoding the reprogramming peptides discussed above.
As such, the great breadth of the claims lack enablement because the claims are not commensurate in scope with the specific guidance provided by the specification.
According to MPEP § 21604:
While the analysis and conclusion of a lack of enablement are based on the factors discussed in MPEP § 2164.01(a) and the evidence as a whole, it is not necessary to discuss each factor in the written enablement rejection. The language should focus on those factors, reasons, and evidence that lead the examiner to conclude that the specification fails to teach how to make and use the claimed invention without undue experimentation, or that the scope of any enablement provided to one skilled in the art is not commensurate with the scope of protection sought by the claims. This can be done by making specific findings of fact, supported by the evidence, and then drawing conclusions based on these findings of fact. For example, doubt may arise about enablement because information is missing about one or more essential parts or relationships between parts which one skilled in the art could not develop without undue experimentation. In such a case, the examiner should specifically identify what information is missing and why one skilled in the art could not supply the information without undue experimentation. See MPEP § 2164.06(a).
Therefore at the time of filing the skilled artisan would need to perform an undue amount of experimentation without a predictable degree of success to implement the invention as claimed.
Relevant Art
Rossi (US 2016/0032317) describes introducing nucleic acids encoding HOXB4 and KLF4 among others to somatic cells to reprogram them into HSC.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARCIA STEPHENS NOBLE whose telephone number is (571)272-5545. The examiner can normally be reached on M-F 9-5:30.
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MARCIA S. NOBLE
Primary Examiner
Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632
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