Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Detailed Action
This action is in response to the papers filed March 28, 2024.
Claim Amendments
Applicant’s amendment to the claims filed 03/28/2024 is acknowledged.
Claims 1-20 have been cancelled.
Claims 21-37 are newly added.
Claims 21-37 are pending and under examination.
Priority
The instant application 18/449,100 was filed on 08/14/2023. This application is a continuation (CON) of 18/068,044 filed 12/19/2022, which is a CON of 17/733,641 filed 04/29/2022, which is a CON of 17/476,208 filed 09/15/2021, which is a CON of 17/152,245 filed 01/19/2021, which is a CON of 16/895,046 filed 06/08/2020, which is a CON of 16/658,374 filed 10/21/2019, which is a CON of 16/288,194 filed 02/28/2019, which is a divisional (DIV) of 15/233,925 filed 08/10/2016 (now, U.S. Patent No. 10,260,048), which is a CON of 14/179,547 filed 02/12/2014 (now, U.S. Patent No. 9,447,382), which is a CON of 13/160,076 filed 06/14/2011 (now, U.S. Patent No. 8,691,574), and claims priority based on U.S. Provisional Applications 61/388,949, filed 10/01/2010, and 61/355,046 filed 06/15/2010.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/12/2024 has been considered.
Claim Objections
Claim 21 is objected to because of the following informalities:
Each claim must begin with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See MPEP 608.01(m). In this case, there is an internal period at the end of step (c) of claim 21, which is considered to be a typographical error. The claim should be amended by changing the period to a semicolon.
Appropriate action is required.
Claim Rejections - 35 USC § 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 21-37 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 claim(s) contains 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims require “exogenous episomal genetic elements... [that] express iPS reprograming factors” are used to reprogram peripheral blood cells into induced pluripotent stem (iPS) cells. Thus, the claims are directed to a broad genus of episomal vectors and manipulative actions that are functionally capable of reprogramming a peripheral blood cell into an iPS cell. The specification teaches that induction of pluripotent stem cells from human somatic cells have only previously been achieved using retroviruses or lentiviral vectors for ectopic expression of reprogramming genes (par. 158). In fact, the specification teaches that targeted integration is not routine, and the conventional random integration may lead to insertional mutagenesis with unpredictable consequences in the resultant iPS cells (par. 159). Furthermore, the specification teaches that there is evidence for the existence of cellular defense mechanisms against foreign DNA which operate by down-regulating transgenes in a process that includes DNA methylation, and viral components may act with other factors to transform cells (par. 160).
The instant specification contemplates using novel methods to generate iPS cells essentially free of exogenous genetic elements using extra-chromsomally replicating vectors (par. 161). The specification contemplates many different episomal vectors (par. 162) and specifically suggests using an EBV-element based system (par. 163). The working examples teach using plasmids that contain the oriP/EBNA-1 plasmid to produce iPS cells (par. 261, 266).
Thus, the specification establishes that the prior art used retroviral vectors or lentiviral vectors (lentiviruses are a type of retrovirus) to produce iPS cells. The specification teaches using a single type of episomal vector, oriP/EBNA-1, and prophetically teaches using other episomal vectors. The specification establishes that reprogramming vectors are not well characterized with respect to specific vectors that will function appropriately to reprogram somatic cells to a pluripotent state. Thus, the genus of “exogenous episomal genetic elements... [that] express iPS reprograming factors” which, when constructed and used as claimed, to produce induced pluripotent stem cells lacks a written description, and as such, there is no indication that applicants had possession of the claimed invention. The claimed invention as a whole is not adequately described if the claims require essential or critical elements which are not adequately described in the specification, and are not conventional in the art as of applicants’ effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the claimed invention in a detailed drawing, or by describing the invention with sufficient, relevant, identifying characteristics (as it relates to the claimed invention as a whole), such that one of skill in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641, 1646 (1998). In the instant case, the breath of the genus of exogenous episomal genetic elements expressing iPS reprograming factors, as functionally claimed, lacks a written description.
The specification does not teach which other exogenous genetic elements that express iPS reprogramming factors, other than using a retrovirus, would result in reprogramming a human peripheral blood cell. The art of Stadtfeld et al. (2008) “Induced pluripotent stem cells generated without viral integration” Science, 322:945-949, of record in IDS, states initially attempts to reprogram mouse tail-tip fibroblasts through the introduction of Oct4, Sox2, KIf4 and c-Myc failed (pg. 946, col. 1-2). Successful reprogramming occurred when adenoviral vectors comprising Sox2, KIf4 and c-Myc delivered the factors to mouse fetal liver cells and mouse tail tip fibroblasts both cell types expressing Oct4 (pg. 946, col. 2-3). Stadtfeld demonstrated reprogramming in adult mouse hepatocytes, infecting them with adenoviral vectors containing the four factors (pg. 946, col. 3,to pg. 947, col. 1). Hepatocytes, as stated by Stadtfeld, were chosen because of their natural compliance to adenovirus infection (page 946, col. 3). Okita et al. (2008) “Generation of mouse induced pluripotent stem cells without viral vectors” Science, 322:949-953, of record in IDS, states the achievement of reprogramming when three factors (Oct4, Sox and KI4) were delivered as a single cistronic sequence with a self-cleaving peptide in an adenoviral vector (page 950, col. 1). Plasmid vectors containing the same three factors as a polycistron were delivered on days 1 and 3, and a separate plasmid vector comprising a c-myc gene was delivered days 2 and 4 (page 950, col. 1). Gonzalez et al. (2009) “Generation of mouse-induced pluripotent stem cells by transient expression of a single nonviral polycistronic vector” Proceedings of the National Academy of Sciences, 106(22), 8918-8922, of record in IDS, describes the delivery of a plasmid comprising Oct4,sox2, KIf4 and c-Myc 2A-peptide linked ORFs by nucleofection into mouse embryonic fibroblast cells (page 8921, col. 1). Gonzalez states two nucleofections were required to obtain iPSCs (page 8921, col. 1). Thus, each of these references teaches methodologies and requirements of those methodologies not disclosed in the specification. Therefore, these methodologies are neither contemplated nor described. The art references are not found to provide the breadth of the claimed genus of episomal vectors expressing iPS reprogramming vectors, and the required methodologies necessarily required for using said episomal vectors in making iPS cells from peripheral blood cells, as claimed.
The specification does not teach any other exogenous episomal genetic elements that express iPS cells, other than using an oriP/EBNA vector, would result in reprogramming a human peripheral blood cell. See working examples. The specification makes clear that the art has not established other vectors that could be used in the claimed methods and the products that are used to reprogram the human peripheral blood cells.
The skilled artisan cannot envision the detailed chemical structure of all of the exogenous episomal genetic elements that express iPS reprograming factors and functionally capable of reprogramming a peripheral blood cell into an iPS cell, that are encompassed by the claims, and, therefore, conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method. Adequate written description requires more than a mere statement that it is part of the invention, and a reference to a potential method of isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481, 1483. In Fiddes, claims directed to mammalian FGFs were found to be unpatentable due to lack of written description for that broad class. The specification only provided the bovine sequence.
The written description requirement necessitates (1) a description of a common core structure shared among the members (species) of the functionally described genus or (2) a disclosure of a representative number of species of the functionally described genus. Thus, claiming all episomal vectors that are functionally capable of reprogramming peripheral blood cells into iPS cells, without disclosing a representative number of species, and without defining what means will do, is not in compliance with the written description requirement. Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the breadth of episomal vectors expressing iPS reprogramming factors, as used in the claimed invention, at the time the application was filed.
Claim Rejections - 35 USC § 103
The following is a quotation of 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 of this title, 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 21-24, 26, 28-37 are rejected under 35 U.S.C. 103(a) as being unpatentable over Loh et al. (2009) “Generation of induced pluripotent stem cells from human blood” Blood, The Journal of the American Society of Hematology, 113(22), 5476-5479, of record in IDS; in view of Yu et al. (2009) “Human induced pluripotent stem cells free of vector and transgene sequences” Science, 324:797-801, of record in IDS; and WO 97/33592 to Pilarski, Linda, of record in IDS.
Regarding claim 21, Loh teaches the production of blood-derived human induced pluripotent stem (iPS) cells from human blood. Particularly, Loh teaches using mobilized peripheral blood cells obtained from Allcells (p. 5476, col. 1). The supplemental materials of Loh provide evidence to show that the CD34+ cells were cultured in IMDM containing 15% fetal bovine serum, supplemented with hSCF, hFlt3L, and Interleukin-3 for 4 days prior to retroviral transduction (p. 1, Cell Culture). The supplemental materials teach that the cells were then transfected with Oct-4, Sox2, Klf4 and Myc retroviral vectors, three days after infection, the cells were split into plates pre-seeded with mouse embryonic fibroblasts and the medium was changed to human ES culture medium 5 days after infection (p. 1, Retroviral production & human iPS induction).
Loh does not teach that the cell population is from one or more subjects whose cells have not been mobilized with extrinsically applied G-CSF or GM-CSF, as claimed.
However, prior to the time of the claimed invention, Pilarski teaches using hyaluron to mobilize hematopoietic cells (pg. 1). In particular, Pilarski teaches that mobilized peripheral blood stem cell collection resulting from the use of G-CSF or GM-CSF is expensive, causes bone pain, and has unknown side effects for normal donors (pg. 4, ll. 24-28), and the use of GM-CSF and/or G-CSF can cause fever, myalgia and erythema (pg. 8, ll. 9-10). Thus, Pilarski teaches using forms of hyaluron (HA) to mobilize hematopoietic cells (pg. 8).
Accordingly, it would have been prima facie obvious to the skilled artisan to modify the teachings of Loh, who inject G-CSF to mobilize peripheral blood (see Supplemental Materials, CD34+ cells collection) and substitute hyaluron (HA), as taught by Pilarski, with a reasonable expectation of success because use of GM-CSF is expensive, causes bone pain, fever, myalgia and erythema in patients.
Loh does not teach using exogenous episomal genetic elements to introduce the iPS reprogramming factors, as claimed.
However, prior to the time of filing, Yu teaches expressing Oct4, Sox2, Nanog and Lin 28 using IRES-mediated expression to coexpress the reprogramming factors in a lentiviral vector, as well as an OriP/EBNA1 vector (pg. 798, col. 2-3).
Accordingly, it would have been prima facie obvious to the skilled artisan to either modify the teachings of Loh and substitute for an exogenous episomal genetic element, such as the OriP/EBNA vector as taught by Yu, for reprogramming a hematopoietic progenitor cell to an iPS cell, with a reasonable expectation of success because Yu reports a 10-fold increase in reprogramming efficiency using IRES-2 mediated expression, and further, using an OriP/EBNA vector as taught by Yu would result in a non-integrating episomal vector. Yu states that, "Human iPS cell derivation previously required vectors that integrate into the genome, which can create mutations and limit the utility of the cells in both research and clinical applications." The art of Loh uses retroviral vectors, which integrate into the genome of the resultant cells. Yu teaches that the oriP/EBNA1 vectors are well-suited for introducing reprogramming human somatic cells because they can be transfected without viral packaging and can be subsequently removed from the cells by culturing in the absence of drug selection (p. 798, col. 1). Thus, Yu provides a clear motivation for the skilled artisan to substitute a genome-integrating vector, which would introduce mutations into iPS cells, such as the retroviral vector taught by Loh, with the OriP/EBNA1 vector taught by Yu, in order to be able to remove the vector and utilize the cells in methods of research and clinical applications.
Since Yu teaches the introduced genetic elements are episomal vectors, which replicate extra-chromosomally in the hematopoietic progenitor cells, said episomal vectors would be removed via culturing of the iPS cells derived from the transformed hematopoietic progenitor cells, as in step “e” of claim 1.
For these reasons, the process according to claim 21 would have been prima facie obvious over the prior art.
Regarding dependent claim 22, although Loh does not teach using a blood sample of about 10 ml in volume, given the teachings of Loh, the skilled artisan would be able to use any volume of blood in order to isolate CD34+ cells in order to produce iPS cells. As noted in In re Aller, 105 USPQ 233 at 235, instructing, 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 the instant case, Loh provides guidance to show that CD34+ cells can be successfully reprogrammed into iPS cells. Therefore, to discover the optimum or workable amount of blood is not considered inventive and no evidence has been presented that using 10 ml of blood was other than routine and that using this amount of blood, the resulting cells would have any unexpected properties, or that the results should be considered unexpected in any way as compared to the closest prior art.
Regarding dependent claim 23, the supplemental materials of Loh teach culturing the cells in IMDM containing 15% fetal bovine serum, supplemented with hSCF, hFlt3L, and Interleukin-3 (see, Cell culture).
Regarding dependent claim 24, the supplemental materials of Loh teach culturing conditions which do not contain a Notch-1 ligand (see, Cell culture).
Regarding dependent claim 26, the supplemental materials of Loh teach the expansion condition prior to transduction do not comprise a matrix (see, Cell culture).
Regarding dependent claim 28, the supplemental materials of Loh teach reprogramming using Oct-4, Sox2, Klf4 and Myc retroviral vectors (see, Retroviral production & human iPS induction).
Regarding dependent claim 29, the supplemental materials of Loh teach that the cells were grown for four days until retrovirus transduction (see, Cell Culture).
Regarding dependent claim 30, the supplemental materials of Loh teach using 5 x 104 CD34+ cells in the reprogramming experiments (see, CD34+ cells collection).
Regarding dependent claims 31-33, the supplemental materials of Loh teach that the cells were transduced and cultured on plates coated with fibronectin fragment CH-296 (RetroNectin®).
Regarding dependent claim 34, the supplemental materials of Loh teach a chemically-defined medium (see, Cell Culture).
Regarding dependent claim 35, the supplemental materials of Loh teach that the cells were only cultured with mouse embryonic fibroblasts (MEFs) three days after transduction (see, Retroviral production and human iPS cell induction), which means that the transduced cells were cultured in feeder-free conditions for three days post-transduction.
Regarding dependent claim 36, the supplemental materials of Loh teach a media composition that is essentially free of feeder-cell conditioned media (see, Cell Culture).
Regarding dependent claim 37, Loh does not teach the media is essentially xeno-free, as claimed.
However, human cell culture using a media that is essentially xeno-free, i.e., free from heterogeneous animal-derived components, was known in the art prior to the effective filing date of the instantly claimed invention (Official Notice taken, if necessary).
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the process of Loh by using a medium that is essentially xeno-free, as known in the art, with a reasonable expectation of success because xeno-free media avoids the risks associated with using a media having xenogeneic components, such as contaminating, animal-originated pathogens.
For these reasons, dependent claims 22-24, 26, 28-37 would have been prima facie obvious over the prior art.
Claim 25 is rejected under 35 U.S.C. 103(a) as being unpatentable over Loh et al. (2009) “Generation of induced pluripotent stem cells from human blood” Blood, The Journal of the American Society of Hematology, 113(22), 5476-5479; Yu et al. (2009) “Human induced pluripotent stem cells free of vector and transgene sequences” Science, 324:797-801; and WO 97/33592 to Pilarski, Linda, as applied to claims 21-24, 26, 28-37 above; in further view of Yuan et al. (2005) “Langerhans cells derived from genetically modified human CD34+ hemopoietic progenitors are more potent than peptide-pulsed Langerhans cells for inducing antigen-specific CD8+ cytolytic T lymphocyte responses” The Journal of Immunology, 174(2), 758-766, of record in IDS.
Loh does not teach that the expansion conditions prior to transformation comprise an extracellular matrix, as claimed.
However, prior to the time of the claimed invention, Yuan teach that culturing CD34+ cells that are undergoing expansion and are grown on RetroNectin® (a recombinant form of fibronectin) supported efficient gene transduction (see p. 762, col. 1, RetroNectin® supports efficient retroviral gene transduction in target CD34+ HPCs undergoing expansion and differentiation into LCs).
Accordingly, it would have been prima facie obvious to the skilled artisan to modify the techniques taught by Loh, to include culturing the CD34+ cells during expansion, on RetroNectin® (i.e., recombinant fibronectin), as taught by Yuan, with a reasonable expectation of success because Yuan teaches that culturing CD34+ cells on RetroNectin® supports the most efficient gene transduction of the CD34+ cells.
Claim 27 is rejected under 35 U.S.C. 103(a) as being unpatentable over Loh et al. (2009) “Generation of induced pluripotent stem cells from human blood” Blood, The Journal of the American Society of Hematology, 113(22), 5476-5479; Yu et al. (2009) “Human induced pluripotent stem cells free of vector and transgene sequences” Science, 324:797-801; and WO 97/33592 to Pilarski, Linda, as applied to claims 21-24, 26, 28-37 above; in further view of Koller et al. (1992) “Effects of synergistic cytokine combinations, low oxygen, and irradiated stroma on the expansion of human cord blood progenitors” Blood, 80(2):403-411, of record in IDS.
Loh does not teach that the expansion conditions have up to 7% oxygen tension, as claimed.
However, prior to the time of filing, Koller teaches the expansion of human hematopoietic progenitor cells at low oxygen (5%) and found that this provided more progenitors and often maintained progenitors longer than those under 20% oxygen (Abstract, Figure 1).
Accordingly, it would have been prima facie obvious to the skilled artisan to modify the techniques of Loh, and expand the hematopoietic progenitor cells by culturing the cells in 5% oxygen, as found in Koller, with a reasonable expectation of success because Koller’s teachings show an improvement in expansion and maintenance of hematopoietic progenitor cells cultured at 5% oxygen.
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 21-37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 10,260,048 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims anticipate the instant claims.
The reference claims are directed to a method for producing human iPS cells from hematopoietic progenitor cells, the method comprising the steps of:
a) providing a cell population of human peripheral blood cells from one or more subjects whose peripheral blood cells have not been mobilized, the population comprising hematopoietic progenitor cells;
b) culturing said population under feeder-free expansion conditions to promote the expansion of said hematopoietic progenitor cells;
c) introducing exogenous episomal genetic elements into said expanded hematopoietic progenitor cells, comprising one or more vectors having an OriP replication origin and a nucleotide sequence encoding EBNA-1 or a derivative thereof, wherein said episomal genetic elements replicate extra-chromosomally in said cells and express iPS reprogramming factors;
d) culturing said expanded hematopoietic progenitor cells in a media that is essentially xeno-free, thereby producing human iPS cells from said hematopoietic progenitor cells; and
e) culturing said iPS cells sufficiently to remove episomal genetic elements
See reference claim 1.
The reference claims further recite:
wherein the cell population is comprised in a blood sample that is up to about 10 ml in volume (claim 2);
wherein the expansion conditions comprise an expansion medium comprising one or more cytokines including SCF, Flt3L, TPO, IL-3, or IL-6 (claim 3);
wherein the expansion conditions do not comprise a Notch-1 ligand (claim 4);
wherein the expansion conditions in step b) comprise a defined extracellular matrix (claim 5);
wherein the expansion conditions in step b) does not comprise a matrix (claim 6);
wherein the expansion conditions in step b) have or the culture in step d) has up to 7% oxygen tension (claim 7);
wherein the reprogramming factors are Sox, Oct, Nanog, Lin-28, Klf4, C-myc (or L-myc), SV40 large T-antigen, or a combination thereof (claim 8);
wherein the step “c” occurs at about days 3, 4, 5 or 6 of the expansion step “b” (claim 10);
wherein the starting number of the expanded hematopoietic progenitor cells in the step “c” is from about 104 to about 105 (claim 11);
wherein the culture in step “d” comprises a defined extracellular matrix (claim 12);
wherein the defined extracellular matrix has a single type of extracellular matrix peptide (claim 13);
wherein the defined extracellular matrix is a human fibronectin fragment (claim 14);
wherein each of the steps are carried out in a chemically defined medium (claim 15);
wherein the media is essentially xeno-free (claim 1).
The reference claims recite that the steps are carried out in a chemically defined medium (claim 15). A “chemically defined medium” is defined as a medium in which the chemical nature of approximately all the ingredients and their amounts are known. Accordingly, a chemically defined medium, as found in the reference claims, is a media that is essentially free of feeder cells or feeder cell-conditioned medium, as found in the instant claims, because otherwise the chemical nature of approximately all the ingredients and their amounts would not be known.
For these reasons, instant claims 21-37 are anticipated by the reference claims.
Claims 21-37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 9,447,382 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims anticipate the instant claims.
The reference claims recite a method for producing human iPS cells from hematopoietic progenitor cells, the method comprising the steps of:
a) providing a cell population of human peripheral blood cells from one or more subjects whose peripheral blood cells have not been mobilized with extrinsically applied G-CSF or GM-CSF, the population comprising hematopoietic progenitor cells;
b) culturing said population under feeder-free expansion conditions to promote the expansion of said hematopoietic progenitor cells;
c) introducing exogenous episomal genetic elements into said expanded hematopoietic progenitor cells, wherein the episomal genetic elements are EBV-based episomal genetic elements, wherein said episomal genetic elements replicate extra-chromosomally in said cells and express iPS reprogramming factors;
d) culturing said expanded hematopoietic progenitor cells in a media that is free of feeder cells or feeder cell-conditioned medium, or in a xeno-free culture, thereby producing human iPS cells from said hematopoietic progenitor cells; and
e) culturing said iPS cells sufficiently to remove episomal genetic elements
See reference claim 1.
The reference claims further recite:
wherein the cell population is comprised in a blood sample that is 1 to 10 ml in volume (claim 2);
wherein the expansion conditions comprise an expansion medium comprising one or more cytokines including SCF, Flt3L, TPO, IL-3, or IL-6 (claim 3);
wherein the expansion conditions do not comprise a Notch-1 ligand (claim 4);
wherein the expansion conditions in step b) comprise a defined extracellular matrix (claim 5);
wherein the expansion conditions in step b) does not comprise a matrix (claim 6);
wherein the expansion conditions in step b) have or the culture in step d) has up to 7% oxygen tension (claim 7);
wherein the reprogramming factors are Sox, Oct, Nanog, Lin-28, Klf4, C-myc (or L-myc), SV40 large T-antigen, or a combination thereof (claim 8);
wherein the step “c” occurs at about days 3, 4, 5 or 6 of the expansion step “b” (claim 9);
wherein the starting number of the expanded hematopoietic progenitor cells in the step “c” is from about 104 to about 105 (claim 10);
wherein the culture in step “d” comprises a defined extracellular matrix (claim 11);
wherein the defined extracellular matrix has a single type of extracellular matrix peptide (claim 12);
wherein the defined extracellular matrix is a human fibronectin fragment (claim 13);
wherein each of the steps are carried out in a chemically defined medium (claim 14);
wherein the media is essentially free of feeder cells (claim 1);
wherein the media is essentially free of feeder-cell conditioned media (claim 1);
wherein the media is essentially xeno-free (claim 1).
For these reasons, instant claims 21-37 are anticipated by the reference claims.
Claims 21-36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 8,691,574 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims anticipate the instant claims.
The reference claims recite a method for producing human iPS cells from hematopoietic progenitor cells, the method comprising the steps of:
a) providing a cell population of human peripheral blood cells from one or more subjects whose peripheral blood cells have not been mobilized, the population comprising hematopoietic progenitor cells;
b) culturing said population under feeder-free expansion conditions to promote the expansion of said hematopoietic progenitor cells;
c) introducing exogenous episomal genetic elements into said expanded hematopoietic progenitor cells, wherein the episomal genetic elements comprise vectors that comprise an OriP replication origin and a nucleotide sequence encoding EBNA-1 or a derivative thereof, wherein said episomal genetic elements replicate extra-chromosomally in said cells and express iPS reprogramming factors; and
d) culturing said expanded hematopoietic progenitor cells in a media that is a defined medium, thereby producing human iPS cells from said hematopoietic progenitor cells.
See reference claim 1. Since the reference claims recite that the introduced genetic elements are episomal genetic elements comprising vectors that comprise an OriP replication origin and a nucleotide sequence encoding EBNA-1 or a derivative thereof, which replicates extra-chromosomally in the hematopoietic progenitor cells, said episomal genetic elements would be removed via culturing of the iPS cells derived from the transformed hematopoietic progenitor cells, as in step “e” of instant claim 1.
The reference claims further recite:
wherein the cell population is comprised in a blood sample that is up to about 10 ml in volume (claim 2);
wherein the expansion conditions comprise an expansion medium comprising one or more cytokines including SCF, Flt3L, TPO, IL-3, or IL-6 (claim 3);
wherein the expansion conditions do not comprise a Notch-1 ligand (claim 4);
wherein the expansion conditions in step b) comprise a defined extracellular matrix (claim 5);
wherein the expansion conditions in step b) does not comprise a matrix (claim 6);
wherein the expansion conditions in step b) have or the culture in step d) has up to 7% oxygen tension (claim 7);
wherein the reprogramming factors are Sox, Oct, Nanog, Lin-28, Klf4, C-myc (or L-myc), SV40 large T-antigen, or a combination thereof (claim 8);
wherein the step “c” occurs at about days 3, 4, 5 or 6 of the expansion step “b” (claim 9);
wherein the starting number of the expanded hematopoietic progenitor cells in the step “c” is from about 104 to about 105 (claim 10);
wherein the culture in step “d” comprises a defined extracellular matrix (claim 11);
wherein the defined extracellular matrix has a single type of extracellular matrix peptide (claim 12); and
wherein the defined extracellular matrix is a human fibronectin fragment (claim 13).
The reference claims recite that the steps are carried out in a defined medium (claim 1). A “defined” medium is defined as a medium in which the nature and amounts of approximately all the components are known. Accordingly, a defined media, as found in the reference claims, is a chemically-defined media, or a media that is essentially free of feeder cells or feeder cell-conditioned medium, as found in the instant claims, because otherwise the nature and amounts of approximately all the components would not be known.
For these reasons, instant claims 21-36 are anticipated by the reference claims.
Claim 37 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 8,691,574 B2, as applied to claims 21-36 above. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been prima facie obvious over the reference claims.
The reference claims do not recite that the media is essentially xeno-free.
However, human cell culture using a media that is essentially xeno-free, i.e., free from heterogeneous animal-derived components, was known in the art prior to the effective filing date of the instantly claimed invention (Official Notice taken, if necessary).
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the process of the reference claims by using a medium that is essentially xeno-free, as known in the art, with a reasonable expectation of success because xeno-free media avoids the risks associated with using a media having xenogeneic components, such as contaminating, animal-originated pathogens.
Claims 21-24, 26, 28-30, 34-37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 8,741,648 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been prima facie obvious over the reference claims.
The reference claims recite a method for producing human iPS cells from hematopoietic progenitor cells, the method comprising the steps of:
obtaining a cell population comprising human CD34+ hematopoietic progenitor cells from a subject whose cells have not been mobilized, wherein the source of the cell population is a blood sample;
culturing the cell population comprising CD34+ hematopoietic progenitor cells in vitro with one or more cytokines to expand the CD34+ hematopoietic progenitor cells therein; and
producing iPS cells from the hematopoietic progenitor cells through the introduction of nucleic acids encoding reprogramming factors, the nucleic acids comprised in one or more episomal vectors, and culturing the cells under defined feeder-free conditions to provide a human iPS cell population that is essentially free of integrated, exogenous viral elements.
See reference claims 1-2, 6. Since the reference claims recite that the introduced genetic elements are episomal vectors, which replicate extra-chromosomally in the hematopoietic progenitor cells, said episomal vectors would be removed via culturing of the iPS cells derived from the transformed hematopoietic progenitor cells, as in step “e” of instant claim 1.
Since the reference claims recite that the cells are cultured under defined, feeder-free conditions, the medium of the reference claims reads on a chemically-defined medium that is essentially free of feeder cells or feeder-cell conditioned medium, as found in the instant claims.
The reference claims recite that the cell population is sourced from a blood sample. However, the reference claims do not recite that the blood sample is a peripheral blood sample, as instantly claimed.
Peripheral blood was known in the art as a readily-available source of blood cells, including hematopoietic progenitor cells, prior to the effective filing date of the instantly claimed invention (Official Notice taken, if necessary).
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the process of the reference claims by taking the blood sample from peripheral blood, as known in the art, with a reasonable expectation of success because peripheral blood is a readily available source of blood cells, which may be collected noninvasively.
For these reasons, instant claim 1 would have been prima facie obvious over the reference claims.
The reference claims further recite:
wherein the cell population is comprised in a blood sample that is about 1 to about 5 ml in volume (claim 3);
wherein the expansion conditions comprise an expansion medium comprising one or more cytokines including SCF, Flt3L, or IL-3 (claim 7);
wherein the reprogramming factors are selected from Sox2, Oct4, Nanog, Lin-28, and Klf4 (claim 1);
wherein each of the steps are carried out in a chemically defined medium (claim 1, “defined, feeder-free conditions”);
wherein the media is essentially free of feeder cells (claim 1, “defined, feeder-free conditions”); and
wherein the media is essentially free of feeder-cell conditioned media (claim 1, “defined, feeder-free conditions”).
The reference claims also do not recite that the expansion conditions comprise a Notch-1 ligand, as in instant claim 24, nor a matrix, as in instant claim 26.
The reference claims do not recite the step “c” occurs at about days 3, 4, 5 or 6 of the expansion step “b”, as recited by instant claim 29.
"[W]here 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).
In this case, the reference claims do not specify the duration of expansion prior to cell transformation. However, given the guidance of the reference claims, one of ordinary skill in the art would have selected a suitable duration for expansion prior to transformation. In particular, the reference claims provide guidance on how CD34+ cells can be successfully reprogrammed into iPS cells. Therefore, to discover the optimum or workable range for the culturing time prior to transformation would require only routine experimentation, and no evidence has been presented showing that the claimed ranges would have yielded any unexpected properties, or that the results should be considered unexpected in any way as compared to those achieved by the process of the reference claims. Thus, absent a secondary consideration, the ranges recited by instant claim 29 would have been prima facie obvious over the reference claims.
The reference claims do not recite the starting number of the expanded hematopoietic progenitor cells in the step “c” is from about 104 to about 105, as recited by instant claim 30.
"[W]here 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). Further, as instructed by MPEP 2144.05, differences in concentration or temperature (in this case, cell number) will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature (in this case, cell number) is critical.
In this case, the reference claims do not specify the cell number achieved prior to transformation. However, given the guidance of the reference claims, one of ordinary skill in the art would have selected a suitable cell number for transformation. In particular, the reference claims provide guidance on how CD34+ cells can be successfully reprogrammed into iPS cells. Therefore, to discover the optimum or workable range for the cell number used in transformation would require only routine experimentation, and no evidence has been presented showing that the claimed ranges would have yielded any unexpected properties, or that the results should be considered unexpected in any way as compared to those achieved by the process of the reference claims. Thus, absent a secondary consideration, the ranges recited by instant claim 30 would have been prima facie obvious over the reference claims.
The reference claims do not recite the media is essentially xeno-free, as recited by instant claim 37.
However, human cell culture using a media that is essentially xeno-free, i.e., free from heterogeneous animal-derived components, was known in the art prior to the effective filing date of the instantly claimed invention (Official Notice taken, if necessary).
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the process of the reference claims by using a medium that is essentially xeno-free, as known in the art, with a reasonable expectation of success because xeno-free media avoids the risks associated with using a media having xenogeneic components, such as contaminating, animal-originated pathogens.
For these reasons, dependent claims 22-24, 26, 28-30, 34-37 would have been prima facie obvious over the reference claims.
Claim 27 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 8,741,648 B2, as applied to claims 21-24, 26, 28-30, 34-37 above; in further view of Koller et al. (1992) “Effects of synergistic cytokine combinations, low oxygen, and irradiated stroma on the expansion of human cord blood progenitors” Blood, 80(2):403-411.
The reference claims do not recite that the expansion conditions have up to 7% oxygen tension, as claimed.
However, prior to the time of filing, Koller teaches the expansion of human hematopoietic progenitor cells at low oxygen (5%) and found that this provided more progenitors and often maintained progenitors longer than those under 20% oxygen (Abstract, Figure 1).
Accordingly, it would have been prima facie obvious to the skilled artisan to modify the process of the reference claims, and expand the hematopoietic progenitor cells by culturing the cells in 5% oxygen, as found in Koller, with a reasonable expectation of success because Koller’s teachings show an improvement in expansion and maintenance of hematopoietic progenitor cells cultured at 5% oxygen.
Claims 25, 31-33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 8,741,648 B2, as applied to claims 21-24, 26, 28-30, 34-37 above; in further view of Yuan et al. (2005) “Langerhans cells derived from genetically modified human CD34+ hemopoietic progenitors are more potent than peptide-pulsed Langerhans cells for inducing antigen-specific CD8+ cytolytic T lymphocyte responses” The Journal of Immunology, 174(2), 758-766.
The reference claims do not recite that the expansion conditions in step “b” or step “d” comprise a defined extracellular matrix, wherein the defined extracellular matrix is a single type of extracellular matrix, wherein the defined extracellular matrix is a human fibronectin fragment, as recited by instant claims 25, 31-33.
However, prior to the time of the claimed invention, Yuan teach that culturing CD34+ cells that are undergoing expansion and are grown on RetroNectin® (a recombinant form of fibronectin) supported efficient gene transduction (see p. 762, col. 1, RetroNectin® supports efficient retroviral gene transduction in target CD34+ HPCs undergoing expansion and differentiation into LCs).
Accordingly, it would have been prima facie obvious to the skilled artisan to modify the process of the reference claims by culturing the CD34+ cells during expansion on RetroNectin® (i.e., recombinant fibronectin), as taught by Yuan, with a reasonable expectation of success because Yuan teaches that culturing CD34+ cells on RetroNectin® supports CD34+ cell culture and the most efficient gene transduction of the CD34+ cells.
Conclusion
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/JAMES JOSEPH GRABER/Examiner, Art Unit 1631