DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election of Group I, claims 58-70, drawn to a method for inducing RBC differentiation via a nucleic acid encoding reprogramming factors HOXA9, ERG, RORA, SOX4, and MYB in the reply filed on September 24, 2025 is acknowledged. Applicant has not indicated traversal; therefore the election is being treated as without traverse.
Claims 71-77 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on September 24, 2025.
Claims 58-70 are being examined on the merits.
Priority
The present application is a is a continuation of U.S. application 16/620,064 filed on December 6, 2019 which is a 35 U.S.C. 371 national stage filing of the International Application No. PCT/US2017/036520, filed on June 8, 2017.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on January 26, 2024 and September 25, 2025 are in compliance with the provisions of 37 CFR 1.97 and are being considered by the examiner.
Applicant is reminded that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
Sequence Compliance
Figure 1A (amino acid sequence of top portion and nucleotide sequence of both portions) and Figure 2A (nucleotide sequences) of the Specification do not conform to sequence rules requiring the use of “SEQ ID NO:” (37 CFR 1.821-1.825).
Where the description or claims of a patent application discuss a sequence that is set forth in the “Sequence Listing” in accordance with paragraph (c) of this section, reference must be made to the sequence by use of the sequence identifier, preceded by “SEQ ID NO:” in the text of the description or claims, even if the sequence is also embedded in the text of the description or claims of the patent application. 37 CFR 1.821 (d). Specifically, the cited section indicates that nucleotide and/or amino acid sequences are an unbranched sequence of 4 or more amino acids or an unbranched sequence of 10 or more nucleotides. Branched sequences are specifically excluded from this definition. Sequences with fewer than four specifically defined nucleotides or amino acids are specifically excluded from this section.
The applicant is reminded that the specification must be amended in order to comply with regulations cited above. All references to sequences in claims and specification should be referred to as “SEQ ID NO:1”, for example. To avoid all doubts of the examiner and to ensure correct interpretation of the claims and specification, the identification of sequences with proper sequence identifiers is required.
Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 66 is objected to because of the following informalities: the claim recites the acronym “DBA” but does not define term prior to use of the acronym. Appropriate correction is required. It is recommended that Applicant amend the claim for clarity such that the first recitation is defined as Diamond Blackfan anemia followed by subsequent use of the acronym DBA.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 67 and 68 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
With regard to claim 67, where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “differentiated” in claim 67 is used by the claim to mean “the process by which a somatic fibroblast becomes an iPS,” while the accepted meaning is “the process by which a progenitor cell becomes a more differentiated cell.” Since a fibroblast is a more differentiated cell type than an iPS, it is not clear how a fibroblast would be able to be differentiated to an iPS. In light of Paras. [00195] and [00221] of the instant specification which recite wherein fibroblasts are “reprogrammed”, it appears that use of the term “differentiated” in the instant claim is a typographical error and that Applicant intends to refer to the process by which a somatic fibroblast is “reprogrammed” or “dedifferentiated” to an iPS. The term is indefinite because the specification does not clearly redefine the term. For the purposes of examination, “differentiated” as recited in specific context of claim 67, and only claim 67, is interpreted as intended to refer to “reprogramming” of somatic fibroblasts to an iPS. Appropriate correction is required.
With regard to claim 68, the term “HPS” in line 2 is not defined by the claim, the specification does not provide a definition of the term, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. As HPS is not recited elsewhere, it is unclear whether HPS is intended to be “HPC” as previously recited or intended to refer to another undefined type of cell. For the purposes of examination, “HPS” as instantly claimed is interpreted as being intended to refer to HPC. Appropriate correction is required.
With regard to claim 68, in view of examiner’s interpretation of HPS as Applicant’s intention to recite HPC, claim 68, which depends from claims 63 and 64, recites the limitation "a HPC" in line 2. There is insufficient antecedent basis for this limitation in the claim as claim 63 recites “the HPC or population there of”. It is recommended that Applicant amend to recite “the HPC” in line with previous claims. Appropriate correction is required.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 58-70 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Doulatov et al. (2017). Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors. Sci. Trans. Med., 9(376), eaah5645, found in IDS dated 1/26/2024, hereafter “Doulatov 2017”).
With regard to claim 58, Doulatov 2017 discloses a transcription factor based method of expanding HPCs derived from iPSCs wherein HPCs were transduced with “5F” lentiviruses (i.e., CD34-5F cells), expanded for two weeks, and differentiated into RBCs (Pg. 2, right col., 1st full para. and Fig 1D). Doulatov 2017 discloses that the 5F lentiviral plasmids comprise HOXA9, ERG, RORA, SOX4 and MYB (Pg. 9, left col., Lentivirus and shRNA plasmids), which is considered to reasonably read on contacting HPCs with a nucleic acid encoding HOXA9, ERG, RORA, SOX4 and MYB for a sufficient time to induce a differentiated RBC.
With regard to claim 59, Doulatov 2017 discloses that HPCs were transduced with 5F lentiviruses and expanded for 2 weeks (Pg. 2, right col., 1st full para.).
With regard to claim 60, Doulatov 2017 discloses that HOXA9, ERG, RORA, SOX4 and MYB are expressed by a lentivirus (Pg. 9, left col., Lentivirus and shRNA plasmids).
With regard to claim 61, Doulatov 2017 discloses that CD34-5F cells exhibit erythroid progenitor maturation (Pg. 1, left col., 1st para.).
With regard to claim 62, Doulatov 2017 discloses that the HPCs transfected with 5F lentivirus (i.e., CD34-5F cells) (Pg. 2, right col., 1st full para.) are CD34+CD45+ (Pg. 9, left col., CD34-5F culture).
With regard to claim 63, Doulatov 2017 discloses that HPCs are derived from iPSCs (Abstract, Pg. 2, right col., 1st full para.).
With regard to claims 64-66, Doulatov 2017 discloses use of iPSCs derived from fibroblasts derived from a patient having an RPS19 mutation (Pg. 1, right col., last para.).
With regard to claim 67, Doulatov 2017 discloses wherein fibroblasts are differentiated to iPSCs in vitro (Pgs. 8-9, Patient samples and reprogramming).
With regard to claim 68, Doulatov 2017 discloses wherein iPSCs are differentiated to EBs in vitro (Pg. 9, Embryoid body differentiation) and wherein EBs are sorted into CD34+CD45+ progenitors, which is considered to reasonably read on HPCs, in vitro (Pg. 9, CD34-5F culture).
With regard to claims 69 and 70, Doulatov 2017 discloses that differentiated CD34-5F RBCs undergo engraftment and enucleation in vivo (Pg. 2, right col., 1st full para.).
Overcoming Rejection by Declaration under 37 CFR 1.130
Doulatov 2017 appears to be Applicant’s own work. Applicant may rely on the exception under 35 U.S.C. 102(b)(1)(A) to overcome this rejection under 35 U.S.C. 102(a)(1) by a (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Examiner’s Comment
Applicant is reminded that affidavits or declarations, such as those submitted under 37 CFR 1.130, 1.131 and 1.132, filed during the prosecution of the prior application do not automatically become a part of the instant application. Where it is desired to rely on an earlier-filed affidavit or declaration, the Applicant should make the remarks of record in this application and include a copy of the original affidavit or declaration filed in the prior application (see MPEP 201.06, IX).
Claims 58-65 and 68-70 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Doulatov et al. (2013, Induction of multipotential hematopoietic progenitors from human pluripotent stem cells via respecification of lineage-restricted precursors. Cell Stem Cell, 13(4), 459-470; hereafter “Doulatov 2013”).
With regard to claim 58, Doulatov 2013 discloses a method of induction of hematopoietic progenitor cells (HPCs) capable of multi-lineage potential and in vitro expansion and which results in engraftment of blood progenitors in vivo (Abstract). Doulatov 2013 discloses that analysis of engraftment following transplantation of blood progenitors confirms RBC differentiation (Pg. 466, right col., 1st para.). Doulatov 2013 discloses a method comprising iPSCs differentiation into HPCs (i.e., CD34+CD45+ progenitors) (Pg. 460, right col., 2nd para., lines 1-6) and subsequent HPCs infection with SOX4, MYB, HOXA9, ERG, and RORA via lentiviral vectors and cultured for 14 days (Pg. 463, right col., 1st para.). Doulatov 2013 further discloses wherein the lentiviral vectors comprise the open reading frames of the transcription factors (Pg. 468, right col., Lentivirus Production and Lentiviral Gene Transfer), which is considered to reasonably read on contacting an HPC or population thereof with a nucleic acid encoding HOXA9, ERG, RORA, SOX4, and MYB for a sufficient time in order to induce RBC differentiation.
With regard to claim 59, Doulatov 2013 discloses that HPCs are infected and cultured for 14 days prior to subsequent assays (Pg. 463, right col., 1st para.).
With regard to claim 60, Doulatov 2013 discloses that the nucleic acid is encoded by a lentiviral vector (Pg. 468, right col., Lentivirus Production and Lentiviral Gene Transfer).
With regard to claim 61, Doulatov 2013 discloses wherein transfected HPCs undergo erythroid maturation (Pg. 466, right col., 1st para.).
With regard to claim 62, Doulatov 2013 discloses that the HPCs are CD34+CD45+ (Pg. 460, right col., 2nd para., lines 1-6).
With regard to claim 63, Doulatov 2013 discloses that HPCs (i.e., CD34+CD45+ progenitors) were derived from iPSCs (Pg. 460, right col., 2nd para., lines 1-6).
With regard to claim 64 and 65, Doulatov 2013 discloses use of an iPSC line, BJ-IPS1, derived from foreskin fibroblasts, which is considered to reasonably read on an iPS derived from a mammalian somatic fibroblast.
With regard to claim 68, Doulatov 2013 discloses use of the fibroblast-derived iPSC line BJ-IPS1 in the method of differentiating iPSCs to HPCs (as detailed in claim 58) and subsequent induction of HSCs derived from the BJ-IPS1 line contacted with SOX4, MYB, HOXA9, ERG, and RORA (Pg. 464, right col., 1st para.). Doulatov 2013’s methods of differentiation of iPSCs to HPCs, transfection of HPCs, and erythroid progenitor culture are all performed in vitro (see Experimental Procedures section), which is considered to reasonably read on differentiation of HPCs in vitro based on the disclosed methods.
With regard to claim 69, Doulatov 2013 discloses that transfected HPCs generate erythroid cells (Pg. 463, right col., 1st and 2nd paras.) but that erythroid maturation/RBC differentiation requires an additional process such as transplantation into the proper microenvironment (Pg. 466, left col. 1st para.) which results in in vivo engraftment, which is the naturally occurring ongoing process following the step of transplantation of the erythroid cells generated by transfected HPCs, of differentiated RBCs (Pg. 466, right col., 1st para.).
With regard to claim 70, Doulatov 2013 discloses wherein differentiated RBCs are CD235a+ CD71+ and enucleated (Pg. 466, right col., 1st para.). CD235a+ is considered to reasonably read on GlyA+.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 66 and 67 are rejected under 35 U.S.C. 103 as being unpatentable over Doulatov 2013 as applied to claims 58, 63, and 64 above in further in view of Garçon et al. (2013, Ribosomal and hematopoietic defects in induced pluripotent stem cells derived from Diamond Blackfan anemia patients. Blood, J. of Amer. Soc. of Hemat., 122(6), 912-921 and Supplemental Methods, hereafter “Garçon”).
With regard to claim 66, as detailed above, Doulatov 2013 teaches method of induction of hematopoietic progenitor cells (HPCs) capable of multi-lineage potential and in vitro expansion and which results in engraftment of blood progenitors in vivo (Abstract). Doulatov 2013 teaches that analysis of engraftment following transplantation of blood progenitors confirms RBC differentiation (Pg. 466, right col., 1st para.). Doulatov 2013’s method comprises differentiation of iPSCs into HPCs (i.e., CD34+CD45+ progenitors) (Pg. 460, right col., 2nd para., lines 1-6) and subsequent HPC infection with lentiviral vectors comprising SOX4, MYB, HOXA9, ERG, and RORA (Pg. 463, right col., 1st para.) and Doulatov 2013 teaches wherein an iPSC line derived from somatic fibroblasts (i.e., BJ-IPS1) is used in the method (Pg. 464, right col., 1st para.). Doulatov 2013 also teaches that iPSCs have been generated from patients having Diamond Blackfan anemia (DBA) and cites Garçon (Pg. 459, Introduction, 1st para.). Further, Doulatov 2013 teaches that iPSC lines from patients with diseases such as DBA have the potential to generate improved models of diseases and platforms for screening of therapeutic drugs, however, existing systems are unable to generate large numbers of transplantable cells from human pluripotent stem cells (Pg. 459, left col. 1st para.), result in cells exhibiting limited engraftment, and generate only small numbers of transplantable cells which cannot be expanded (Pg. 459, left col., 2nd para.).
Doulatov 2013 does not teach generation of iPSCs from fibroblasts isolated from patients having a ribosomal disorder, DBA, or a mutation in RSP19.
Garçon teaches generation of iPSCs from fibroblasts isolated from DBA patients having mutations in RSP19 (Abstract). Additionally, Garçon teaches that somatic cells which are reprogrammed into iPSCs provide new opportunities for studies of DBA and a potential strategy for cellular therapy (Pg. 912, right col., 2nd para.).
Therefore, it would have been obvious to one having ordinary skill in the art, before the effective filing date of the claimed invention, to use somatic fibroblasts from a patient having DBA and/or a mutation in RSP19 which can be reprogrammed into iPSCs as taught by Garçon in the method of inducing RBC differentiation comprising contacting HPCs with a nucleic acid encoding HOX9A, ERG, RORA, SOX4, and MYB wherein the HPCs are derived from iPSCs derived from somatic fibroblasts as taught by Doulatov 2013 with a reasonable expectation of success. A skilled artisan would have been motivated to make this combination in order to generate DBA-specific HPCs which are capable of being expanded and transplanted thereby providing an improved model for the study of DBA and therapeutic DBA treatments.
With regard to claim 67, as detailed above, Doulatov 2013 teaches method of induction of hematopoietic progenitor cells (HPCs) capable of multi-lineage potential and in vitro expansion and which results in engraftment of blood progenitors in vivo (Abstract). Doulatov 2013 teaches that analysis of engraftment following transplantation of blood progenitors confirms RBC differentiation (Pg. 466, right col., 1st para.). Doulatov 2013’s method comprises differentiation of iPSCs into HPCs (i.e., CD34+CD45+ progenitors) (Pg. 460, right col., 2nd para., lines 1-6) and subsequent HPC infection with lentiviral vectors comprising SOX4, MYB, HOXA9, ERG, and RORA (Pg. 463, right col., 1st para.) wherein the method steps are performed in vitro (See Experimental Procedures section). Further, Doulatov 2013 teaches wherein an iPSC line derived from somatic fibroblasts (i.e., BJ-IPS1) is used in the method (Pg. 464, right col., 1st para.) and that iPSCs have been generated from patients with hematologic diseases, including Diamond Blackfan anemia (DBA), citing Garçon (Pg. 459, Introduction, 1st para.).
While Doulatov 2013 does teach use of an iPSC cell line derived from fibroblasts, Doulatov 2013 is silent as to the method steps of reprogramming the fibroblasts into iPSCs.
Garçon teaches generation of iPSCs from skin fibroblasts isolated from DBA patients as well as skin fibroblasts isolated from normal individuals (Pg. 913, Results, lines 1-5) wherein reprogramming of fibroblasts into iPSC lines was performed in vitro (Garçon Supplemental Methods, Creation and differentiation of iPSCs from DBA patients).
Therefore, it would have been obvious to one having ordinary skill in the art, before the effective filing date of the claimed invention, to apply the process of reprogramming fibroblasts into iPSCs in vitro as taught by Garçon prior to use of Doulatov 2013’s method of inducing RBC differentiation comprising contacting HPCs with a nucleic acid encoding HOX9A, ERG, RORA, SOX4, and MYB wherein the HPCs are derived from iPSCs derived from somatic fibroblasts with a reasonable expectation of success. A skilled artisan would have been motivated to make this combination as the subsequent steps in the method as taught by Doulatov 2013, i.e., generation of HPCs from iPSCs, are also performed in vitro. Thus, performing both reprogramming of fibroblasts to iPSCs in vitro as well as differentiation of generated iPSCs to HPCs in vitro would decrease complexity by reducing additional method steps and allow for increased control over the experimental method.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIN V PAULUS whose telephone number is (571)272-6301. The examiner can normally be reached Mon-Fri 8 AM-5 PM.
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/ERIN V PAULUS/Examiner, Art Unit 1631
/ARTHUR S LEONARD/Examiner, Art Unit 1631