DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Election/Restrictions
Applicant’s election without traverse of Group I claims 57-68 in the reply filed on 11/18/2025 is acknowledged.
Claims 69-74 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/18/2025.
Claim interpretation
The claims are product by process claims. The process by which the claimed cells are obtained can be given patentable weight if the process alters the structure of the cells. Most claims doe not limit the nucleic acid vector to one that inserts into the genome. Thus, these embodiments do not result in a cell that has an altered genome. Claims that limit the vector used to retroviral vectors (claim 63) or a vector that integrates into the genome (claim 62) do not actively require the vector have been inserted into the genome and encompass embodiments where the vector is lost after reprogramming.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 57-68 are rejected under 35 U.S.C. 101 because the claimed invention is not directed to patent eligible subject matter. Based upon an analysis with respect to the claims as a whole, claim(s) 57-62,64-68 are determined to be directed to a natural product and do not recite something significantly different than the natural product. The rationale for this determination is explained below:
Claims 57-68 are directed to immune cell derived iPSCs. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. The iPSCs are derived using an vectors that can be lost from the cells in culture, resulting in iPSCs and derivative cells that do not differ in structure from ESCs (see below), which are products of nature. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception. More detailed analysis is set forth below.
The Office published Office’s new guidance document entitled 2014 Interim Guidance on Patent Subject Matter Eligibility (Interim Eligibility Guidance), published December 16, 2014. Applicant is directed to the Federal Register at page 74621.
The Office published Office’s new guidance document entitled 2019 Revised Patent Subject Matter Eligibility Guidance, published January 7, 2019. Applicant is directed to the Federal Register, Volume 4, No. 4, pages 50-57 at page 74621.
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Step 1: The claim is directed to a composition of matter (an iPSC cell line; Step 1: Yes).
Step 2A – Prong 1: Examiners evaluate whether the claim recites a judicial exception. The composition of matter (a cell) is directed to a natural phenomenon (Step 2A, prong 1: Yes). MPEP §2106.04(b)(I) which shows that isolated DNA, cloned animals are considered natural phenomenon, for example.
Step 2A- Prong 2: Examiners evaluate whether the claim recites additional elements that integrate the exception into a practical application of that exception. This judicial exception is not integrated into a practical application because they do not recite additional elements that integrate the judicial exception into a practical application as no other elements are recited.
Step 2B- Step 2B the claim is evaluated as to whether it recites additional elements that amount to significantly more than the judicial exception.
Based on the guidance, The Supreme Court has identified a number of considerations for determining whether a claim with additional elements amounts to significantly more than the judicial exception itself. Limitations that may be enough to qualify as ‘‘significantly more’’ when recited in a claim with a judicial exception include: Improvements to another technology or technical field; improvements to the functioning of the computer itself; applying the judicial exception with, or by use of, a particular machine; effecting a transformation or reduction of a particular article to a different state or thing; adding a specific limitation other than what is well-understood, routine and conventional in the field, or adding unconventional steps that confine the claim to a particular useful application; or other meaningful limitations beyond generally linking the use of the judicial exception to a particular technological environment.
Limitations that were found not to be enough to qualify as ‘‘significantly more’’ when recited in a claim with a judicial exception include: Adding the words ‘‘apply it’’ (or an equivalent) with the judicial exception, or mere instructions to implement an abstract idea on a computer; simply appending well-understood, routine and conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, e.g., a claim to an abstract idea requiring no more than a generic computer to perform generic computer functions that are well-understood, routine and conventional activities previously known to the industry; adding insignificant extra-solution activity to the judicial exception, e.g., mere data gathering in conjunction with a law of nature or abstract idea; or generally linking the use of the judicial exception to a particular technological environment or field of use.
In the instant case, the limitations of the claims do not impose limits on the claim scope such that they are not markedly different in structure from a naturally occurring product. In particular, claim 17 is directed to an iPSC which is accepted as being indistinguishable from an ESC. In the instant case, the DNA used to derive the iPSCs is lost and no longer present in the iPSCs. Mallon (2014, Stem Cell Research, 12:376-386) discusses that there are no significant differences between ESCs and iPSCs. There are no additional elements in the claims.
The Federal Register at p. 74623 provides guidance as to analysis of nature-based products. In the instant case, claims 57-68 are directed to a iPSCs which are accepted as being indistinguishable from an ESC (see Mallon, cited above).
The iPS cells of the claimed invention are natural products that are not markedly different from naturally occurring pluripotent cells (ESC). ESCs are natural products as set forth below.
Gross Anatomy Level
With respect to ES cells from the vantage of gross anatomy, the art supports that ES cells are naturally occurring cells present in the inner cell mass. Specifically the art teaches that embryonic stem cells are isolated from the inner cell mass of blastocysts. See also, Thomson, Science, 282: 1145-1147, 1998 at p. 1145, col. 2; p. 1145, #6, for example.
Cellular Level
With respect to hES cell from the vantage of the cellular level, the art teaches that hES cells are derived directly from the inner cell mass (ICM). Specifically, Reubinoff et al. (2000, Nature Biotechnology, Vol. 18, pgs. 399-404) teach that the late ICM is first isolated from a human blastocyst, the isolated ICM is then plated onto a feeder layer and that within several days hES cells are present in clumps in sufficient number to be mechanically dissociated (pg. 399 col. 2 parag. 2 lines 1-9). Regarding the clumps, Reubinoff teach that ICM-like clumps were removed six to eight days after initial plating of the ICM, and that these clumps propagated in a layer to form a colony of stem cells (pg. 403 col. 2 parag. 1 lines 21-25).
Molecular Level
With respect to hES cell from the vantage of the molecular level, the art teaches that hES cells may be a select subpopulation of cells isolated from the ICM. Specifically, Reijo et al. (2009, Differentiation, Vol. 78, pgs. 18-23) teach in Fig. 3 (reproduced below) that there are three potential pathways for the establishment of hES cells:
(i) selective expansion of a distinct subpopulation,
(ii) differentiation of epiblast cells and
(iii) reversion to pre-blastocyst stage embryonic cells .
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Regarding selective expansion of a distinct subpopulation of ICM cells, Reijo teaches that “One model is that hESCs maybe the product of selective expansion of a subset of ICM cells that possess the ability to self-renew, similar in potential to cells of the preblastocyst (cleavage stage) embryo. This model is supported by the observation that like early embryonic cells, hESCs may be capable of differentiating to extraembryonic trophectoderm, in addition to somatic and germ line derivatives, in vitro” (pg. 21 col. 2 parag. 2 lines 3-9). Therefore, hES cells as well as the indistinguishable iPSCs are considered a judicial exception.
This is further supported by the remarks of Dr. Lyle Armstrong to the UK House of Parliaments’ Select Committee on Science and Technology, Fifth Report of Session 2006-07, Volume II, pages 76-77, 5 April 2007,
Dr. Armstrong stated the following:
“ESC[s] are derived from very early pre-implantation stage embryos which are obtained from IVF clinics subject to licensing by the HFEA. A typical blastocyst stage embryo is shown in figure 1 [copied below] and ESC are derived from the area highlighted by an arrow which is called the inner cell mass. This small group of cells would normally produce the entire organism (the other cells are destined to become parts of the placenta), but at this point in time they are all equally capable of becoming nerve, muscle, blood, etc. and so we think of them as being pluripotent. ESC[s] effectively represent a “snapshot” of this stage of development which we can maintain indefinitely by choosing culture media that prevent the cells from differentiating as they would in the developing embryo.” [Examiner’s emphasis]
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Lai et al., Proc Natl Acad Sci U S A. 2012 Mar 6; 109(10):3772-7, adds: “Cells in the ICM are pluripotent during a narrow window of development; however, pluripotency can be maintained almost indefinitely in culture under the appropriate conditions.” See page 3772, col. 1.
Dominiguez-Bendala et al., Handbook of Stem Cells, Chapter 70: Islet Cell Therapy and Pancreatic Stem Cells, pages 835-853, 2013, echo the remarks by Dr. Armstrong and the teachings of Lai by stating "ES cells are an artificially frozen snapshot of ICM cells found at the blastocyst stage." See page 840, col. 2.
In view of these references, it is clear that a hESC’s ability to maintain an undifferentiated state is not a novel characteristic of the cell, but rather, a result of the conditions in which the cell is cultured therein. Therefore, hESCs are natural products that are indistinguishable, and are not markedly different, from the claimed iPSCs. Likewise, the blood cells derived from the iPSCs fail to differ from blood cells found in nature.
To this point, the Examiner cites In re Roslin Institute (Edinburgh), No. 2013-1407 (Fed. Cir. May 8, 2014), pages 1-12. In Roslin, the Federal Circuit affirmed the Patent Trial and Appeal Board’s rejection of claims for a cloned animal under 35 USC §101. In particular, the Board stated that the claimed clones “may be called a composition of matter or a manufacture” as required by § 101, J.A. 18, it concluded that the claimed subject matter was ineligible for patent protection under § 101 because it constituted a natural phenomenon that did not possess “markedly different characteristics than any found in nature.” J.A. 21. See p. 4 of the Decision.
As noted in the Federal Register, at p. 74623, col. 1, ¶3, provides guidance for analysis of nature-based products stating that, “When the nature-based product is produced by combining multiple components, the markedly different characteristics analysis should be applied to the resultant nature-based combination, rather than its component parts.”
The question we face is whether or not these purported differences render the cells markedly different. Non-limiting examples of the types of characteristics considered by the courts when determining whether there is a marked difference include: (1) Biological or pharmacological functions or activities, e.g., a bacterium’s ability to infect leguminous plants, or the protein encoding information of a nucleic acid; (2) Chemical and physical properties, e.g., the alkalinity of a chemical compound, or the ductility or malleability of metals; (3) Phenotype, including functional and structural characteristics, e.g., the shape, size, color, and behavior of an organism; and (4) Structure and form, whether chemical, genetic or physical, e.g., the physical presence of plasmids in a bacterial cell, or the crystalline form of a chemical.
Along these lines, Choi et al. (Nature Biotechnology 33, 1173–1181, 2015) genetically matched hESC and hiPSC lines to assess the contribution of cellular origin (hESC vs. hiPSC), the Sendai virus (SeV) reprogramming method and genetic background to transcriptional and DNA methylation patterns while controlling for cell line clonality and sex. Choi teaches 49 differentially expressed genes (DEGs) were detected between genetically matched hESCs and hiPSCs. To determine whether the DEGs had functional consequences, Choi initially focused on two DEGs, LDHA and SLC2A1 (also known as GLUT1), because of their strong basal expression in hESCs and reduced expression in all hiPSCs. Choi teaches both gene products are involved in energy metabolism; LDHA plays an important role in glycolysis by catalyzing the conversion of pyruvate to lactate whereas SLC2A1 facilitates glucose uptake in cells. Of note, Choi teaches human pluripotent stem cells produce energy through glycolysis. Thus, based on the downregulation of these two genes in all examined hiPSC lines compared to hESC lines by RNA-seq and qPCR analyses (Fig. 3e), Choi hypothesized that hiPSC lines might be less glycolytic than hESC GFP lines. However, Choi observed neither lactate production nor glucose uptake levels differed between genetically matched hiPSC and hESC GFP lines (Fig. 3f). Further, there was no difference in LDHA protein levels despite the observed transcriptional differences (Fig. 3g and Supplementary Fig. 3).
Moreover, Choi teaches the DEGs IRX2 and DPP10 have been linked to neural development and psychiatric diseases and IRX2 suppression reportedly impairs hESC differentiation into neural progenitors. In the genetically matched hESC and hiPSC lines, Choi observed silencing of IRX2 and DPP10 in some of the hiPSC lines and none of the hESC lines (Fig. 4b). Thus, based on the silencing of IRX2 and DPP10 in some of the hiPSC lines, it would be reasonable to conclude that hiPSC differentiation into neural progenitors would be impaired. On the contrary, Choi teaches IRX2 and DPP10 silencing in hiPSCs did not affect the cells' potential to differentiate into neuroectodermal cells, as determined by RNA expression analysis for NESTIN, SOX1, PAX6, and FOXG1, well-established markers of neuroectoderm differentiation from human pluripotent stem cells (Fig. 4e). Therefore, while Choi teaches differences between pluripotent embryonic stem cells and induced pluripotent stem cells, those differences were not markedly different, as defined by the courts.
Likewise, In In re Roslin, Roslin attempted to argue that their cloned mammals were distinguishable from original donor mammals because of differences in mtDNA. In this argument, Roslin stated that the cloned sheep (Dolly)’s mtDNA came from the oocyte used to create her, not her donor mammary cell. Roslin argued that this difference in mitochondrial FNA renders its product patent eligible. Notably, the decision states:
“But any difference in mitochondrial DNA between the donor and cloned mammals is, too, unclaimed. Furthermore, Roslin’s patent application does not identify how differences in mitochondrial DNA influence or could influence the characteristics of cloned mammals.” See pages 10-11, bridging paragraph of the Decision.
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 –
(a) the invention was known or used by others in this country, or patented or described in a printed publication in this or a foreign country, before the invention thereof by the applicant for a patent.
(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.
(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) 57-68 is/are rejected under pre-AIA 35 U.S.C. 102 (a) and (e) as being anticipated by WO/2008/124133 (IDS).
‘516 teaches reprogramming somatic cells, including B and T cells using exogenously introduced Oct4, Sox2, Klf-4, c-Myc and C/EBPa encoded on retroviral vectors (see pages 11-12, claim 57-63). ‘516 teaches obtaining a population of pluripotent cells comprising “at least 70% pluripotent cells derived from reprogrammed differentiated somatic cells” (page 14, claim 64). The cells are in culture and therefore are in a medium (claims 65-66,68). ‘516 also teaches that the cells are patient-specific (page 29, claim 67)
Applicant is referred to the claim interpretation set forth above. The claims, being product by process claims, encompass a pluripotent stem cell made by any method. Claims such as claim 70 that require the starting cell be a T cell or B cell encompasses iPSCs with a genome rearrangement that occurs during lymphocyte differentiation. Claim 70, however, encompasses macrophages, whose genome does not differ from other somatic cells. Because the vector encoding the reprogramming factors can be lost through culture following reprogramming, the claimed specifics of the vector are not given weight.
Claim(s) 57-68 is/are rejected under pre-AIA 35 U.S.C. 102 (a) as being anticipated by Hanna (2008, Cell, 133:250-264; IDS).
With regard to claims 57-Hanna teaches reprogramming B cells using exogenously introduced Oct4, Sox2, Klf-4, c-Myc and C/EBPa encoded on multiple (claim 59) lentiviral vectors (see pages Figure 1, claim 57-5963,65). Hanna teaches that the immunoglobulin loci in the iPS cells are rearranged (see page 257, left column, 58). Hanna does not teach inclusion of C/EBPa (claim 60-62) or multiple coding sequences on a single nucleic acid separated by self-cleaving peptides. However, these claims can be interpreted as set forth above where the vector is lost following reprogramming and thus the structure of the vector used to reprogram is not present in the claimed pluripotent cell. Clonal populations are cultured in medium, meeting the limitations of claims 64-66 and 68. With regard to claim 67, “patient-specific” is an intended use. Cells derived from any individual are specific to that individual.
Claim(s) 57-68 is/are rejected under pre-AIA 35 U.S.C. 102 (b) as being anticipated by Takahashi (2006, Cell, 126:663-676; IDS).
Takahashi teaches reprogramming fibroblasts using exogenously introduced Oct4, Sox2, Klf-4, c-Myc encoded on retroviral. ‘516 teaches clonal populations which meet the limitation of 70% (Figure 1, page 665, claim 64). The cells are in culture and therefore are in a medium (claims 65-66,68). Takahashi also teaches that the cells are patient-specific (page 673, claim 67)
Applicant is referred to the claim interpretation set forth above. The claims, being product by process claims, encompass a pluripotent stem cell made by any method. Claims that require the starting cell be a T cell or B cell encompasses iPSCs with a genome rearrangement that occurs during lymphocyte differentiation but the claims (58 and 70) also recite “macrophage” which does not comprise a genomic rearrangement. Because the vector encoding the reprogramming factors can be lost through culture following reprogramming, the claimed specifics of the vector are not given weight.
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.
Claim 57-68 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 9,382,515 (IDS). Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims are also drawn to pluripotent stem cells. The patented claims recite characteristics that are inherent and defining of pluripotent cells and thus, are present in the pending claimed cells. As set forth above, process limitations of the pending claims are not given weight.
Conclusion
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VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/ Primary Examiner, Art Unit 1632