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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 31 July 2026 has been entered.
Election/Restrictions
Claims 22-23 and 26-27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 23 September 2025.
Applicant added new claims 29-33, in the amendments filed 14 January 2026, which ultimately depend from claim 1. Therefore, these claims have been added to the previously elected group 1. Group 1 now comprises claims 1-6, 8-11, 13, 15-16, 18-19, 21, and 29-33.
Applicant added new claim 34, in the amendments filed 14 January 2026, which depends from withdrawn claim 26, therefore, claim 34 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Applicant added new claim 35, in the amendments filed 31 July 2026, which depends from claim 33, therefore, claim 35 the claim has been added to the previously elected group 1. Group 1 now comprises claims 1-6, 8-11, 13, 15-16, 18-19, 21, 29-33, and 35.
Claim Status
Claims 7, 12, 14, 17, 20, 24-25, and 28 were previously canceled, claim 34 is newly canceled, claims 1, 22, and 29-31 are currently amended, claim 35 is new, claims 22-23, 26-27, and 34 are withdrawn as being drawn to a nonelected invention, and claims 1-6, 8-11, 13, 15-16, 18-19, 21, 29-33, and 35 have been considered on their merits.
Withdrawn Rejections/Response to Traversal
The claim objections have been withdrawn due to Applicant’s amendments to the claims.
Applicant’s arguments, see the remarks, filed 31 July 2026, with respect to the rejections of the claims under 35 U.S.C. § 102 and 35 U.S.C. § 103 have been fully considered and are persuasive. Specifically, due to the amendment to the claims to remove SEQ ID NO: 2 and SEQ ID NO: 6. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Orkin et al.
Thus, the claim rejection under 35 U.S.C. § 102 and 35 U.S.C. § 103 have been withdrawn in view of Applicant’s amendments to the claims.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6, 8-11, 13, 15, 16, 18-19, 21, 29-30, and 32 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. “Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement.” Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
For claims drawn to a genus, possession may be shown (for example) through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A “representative number of species” means that the species which are adequately described are representative of the entire genus, and is an inverse function of the skill and knowledge in the art. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly. If a representative number of adequately described species are not disclosed for a genus, the claim to that genus must be rejected as lacking adequate written description under 35 U.S.C. 112(a). Also see MPEP § 2163.
The scope of the claims does not commensurate with the possession demonstrated by the disclosure with regard to the extremely large number of variants broadly encompassed by the claims. Assuming a sequence of 300 nucleotides, which is less than any of the disclosed sequences, a variation of 50% identity could result in 4150 (2 x 1090) possible species.
Regarding claim 1, since the nucleic acid sequence of an enhancer element determines its structural and functional properties, predictability of which changes can be tolerated in a enhancer elements’ nucleic acid sequence and obtain the desired activity requires a knowledge of and guidance with regard to which nucleic acids in the enhancer elements’ sequence, if any, are tolerant of modification and which are conserved (i.e., expectedly intolerant to modification), and detailed knowledge of the ways in which the enhancer elements’ structure relates to its function. Thus, the claim is drawn to a very large genus of nucleic acid molecules comprising the claimed function.
Neither the specification nor the prior art establishes a structure-function relationship wherein a functional variant of an expression cassette comprising at least one copy of an enhancer element, wherein the enhancer element comprises a nucleotide sequence at least 50% identical to the nucleotide sequence set forth in any one of SEQ ID NOs: 1, 3-5, and 7-10, would maintain the structure as claimed with any degree of predictability.
The instant specification does not provide any guidance as to which 50% of the nucleotides can be modified to arrive at a functional enhancer element, therefore, the specification does not disclose any embodiments which would be encompassed within the pending claim. The specification does not identify what changes, mutations, fragments, etc. could be made to the enhancer element, and that would be encompassed by the structural limitations of the expression cassette of claim 1, and would predictably result in the claimed function of an enhancer element as disclosed in any one of SEQ ID NOs: 1, 3-5, and 7-10. As such, the instant specification does not provide a sufficient representative sampling of structures that are at least 50% identical to any one of SEQ ID NOs: 1, 3-5, and 7-10 that are capable of providing for said function as claimed.
Regarding claim 29 and 30, these claims further narrow the percent identity to 90 and 95% respectively, however, 90% or 95% identity to any one of SEQ ID NOs: 1, 3-5, and 7-10 would still result in at least 430 or 415 possible species. Since the nucleic acid sequence of the nucleic acid construct determines its structural and functional properties, predictability of which changes can be tolerated in a nucleic acid sequence and obtain the desired activity requires a knowledge of and guidance with regard to which nucleic acids in the nucleic acid sequence, if any, are tolerant of modification and which are conserved (i.e., expectedly intolerant to modification), and detailed knowledge of the ways in which the nucleic acid sequence structure relates to its function. Thus, the claim is drawn to a large genus of nucleic acid molecules comprising the claimed function.
The art is unpredictable. Post art Arnold et al. (Transcription 2023, Vol.14, Nos. 1-2, 68-87) teach enhancers are DNA-encoded regulatory elements and every enhancer is present in every cell, and it is the transcription factor-driven changes in enhancer activity that drive cell type-specific gene expression programs (pp. 75-76). Arnold teaches sequence-specific transcription factors are thought to bind target enhancers based on the presence and accessibility of high affinity binding motifs of typically 6 to 12 bp in length and binding sites often co-occur with secondary motifs, motif extensions, or flanking A- or T-rich stretches (p. 76). Arnold teaches their order, orientation and spacing relative to each other appear to follow specific, so far poorly understood syntax rules (p. 76). Arnold teaches in addition to motif recognition, intrinsically disordered regions commonly contained with TFs and DNA shape can contribute to DNA binding (p. 76). Thus, the prior art cannot be relied upon for making up for the deficit of the instant specification with regard to a sufficient representative number of species that are at least 50% identical to any one of SEQ ID NOs: 1, 3-5, and 7-10 which would provide a predictable function as Arnold highlights the structure function relationship as it relates to sequence of enhancer regions.
While recombinant and mutagenesis techniques are known, it is not routine in the art to screen for multiple substitutions or multiple modifications, as encompassed by the instant claims, and the positions within a nucleic acid construct where nucleic acid modifications can be made with a reasonable expectation of success in obtaining the desired activity/utility are limited in any enhancer and the result of such modifications is unpredictable. In addition, one skilled in the art would expect any tolerance to modification for a given promoter to diminish with each further and additional modification, e.g. multiple substitutions.
The specification does not support the broad scope of the claims which encompass all modifications of an expression cassette comprising a enhancer element, or a functional variant of said enhancer element because the specification does not establish: (A) regions of the nucleic acid sequence structure which may be modified without effecting its function; (B) the general tolerance of enhancer elements, or a functional variant of said enhancer element to modification and extent of such tolerance; (C) a rational and predictable scheme for modifying any nucleic acid residues with an expectation of obtaining the desired biological function capable of the intended results; and (D) the specification provides insufficient guidance as to which of the essentially infinite possible choices is likely to be successful.
Thus, applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims. Without sufficient guidance, determination of exact nature of the nucleic acid sequences having at least 50% identity with any one of SEQ ID NOs: 1, 3-5, and 7-10 are unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731,8 USPQ2nd 1400 (Fed. Cir, 1988).
Accordingly, neither the specification nor the prior art establishes a known structure-function relationship wherein the genus of structures that are at least 50% identity with any one of SEQ ID NOs: 1, 3-5, and 7-10 and are capable of providing for the function as claimed with any predictability. The prior art highlights the structural importance of enhancer elements, which would be tied to the structure function relationship. In this case, the skilled artisan would not have reasonably concluded at the time of the invention that application was in possession of the invention as claimed.
Claims 2-6, 8-11, 13, 15, 16, 18-19, 21, 29-30, and 32 are included in the rejection because they depend from claim 1.
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 1-2, 16, 18-19, 21, and 29-30 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more.
This is a new rejection.
Claim 1 recites an expression cassette comprising at least one enhancer element comprising nucleotide sequence at least 50% identical to any one of SEQ ID NO: 1, 3-5, and 7-10. Thus, the claims as a whole fall within one of four statutory categories, i.e., a composition of matter (Step 1: YES).
Step 2A, Prong One: evaluation whether the claim recites a judicial exception.
Claim 1 recites an expression cassette, which is broadly interpreted as including a chromosome. The claimed sequences are all 100% identical to sequences found in the human genome. SEQ ID NO: 1 is 100% identical to a sequence within the PPARA gene, SEQ ID NO: 3 is identical to a sequence within the STAM gene, SEQ ID NO: 4 is 100% identical to the complement of a sequence of the EH38E2030714 proximal enhancer on chromosome 2, SEQ ID NO: 5 is 100% identical to a sequence within the complement of the BCL11A gene, SEQ ID NO: 7 is 100% identical to a sequence within the ADIPOR1 gene, SEQ ID NO: 8 and 9 are both 100% identical to a sequence within the PVT1 gene, and SEQ ID NO: 10 is 100% identical to a sequence of human chromosome 7, GRCh38/hg38. Therefore, all of the SEQ ID NOs are considered nature-based products as the closest natural counterparts are chromosomes comprising the sequences of the human genome with no difference in structure, function, or other characteristics, thus, the claimed expression cassette is a product of nature exception. Association for Molecular Pathology v. Myriad Genetics Inc., 569 U.S. 576, 589-90 (2013) (naturally occurring things are “products of nature” which cannot be patented). Accordingly, the claims recite judicial exceptions (Step 2A, Prong One: YES).
Step 2A, Prong Two: eligibility analysis to determine whether the claim as a whole integrates the recited judicial exception into a practical application of the exception.
The claims do not integrate the product into a practical application because the claim is to the product an expression cassette comprising a nucleotide sequence, per se, without additional element that utilizes the judicial exception in any application. (Step 2A, Prong 2: No).
Step 2B: evaluation whether the claims as a whole amount to significantly more than the recited exception.
Claim 2 recites wherein the enhancer element comprises an erythroid transcription factor binding site selected from GATA1, TAL1, and KLF1. These binding sites would be considered inherently present as the sequences are all 100% identical to the natural counterparts.
Claims 16, 18-19, 30-31, and 33 are directed to a cell comprising the expression cassette, since the expression cassette can be interpreted as a chromosome, a cell comprising the expression cassette also reads as a product of nature.
Claim 21 includes a pharmaceutically acceptable carrier. This carrier could also read as a product of nature, such as water. Even if this was not considered a product of nature, this additional element is not sufficient to amount to significantly more than the judicial exception because it does not add a meaningful limitation.
Claim 29 further limits the sequence identity to 90% identical.
Therefore, these claims do not add a meaningful limitation making the expression cassette more than a product of nature.
Based on the above analysis, claims 1-2, 16, 18-19, 21, and 29-30 do not disclose subject matter eligible under 35 U.S.C 101.
The dependent claims not discussed in the above analysis are not included in the rejection because they comprise elements which amount to significantly more than the judicial exception.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 1-2, 5-6, 8-10, 16, 18-19, and 29-30 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Orkin et al. (US 2015/0132269 A1, published 14 May 2015) as evidenced by Sher et al. (Biochemistry 1993, 32, 5598-5604) and NCBI Reference Sequence: NM_001393947.1, published 1993.
This is a new rejection necessitated by Applicant’s amendments to the claims.
Regarding claims 1-2 and 29, Orkin teaches genome engineering particularly targeted modifications of the genome of a hematopoietic cell (para. [0002]). Orkin teaches SEQ ID NO: 254 which comprises the sequence which is 100% identical (claim 29) to the complement of SEQ ID NO: 5. See sequence search results from 18 September 2026, file us-17-793-793-5.rnpbm. Since BCL11A is found on the negative strand, one of ordinary skill would know to utilize the complement of the sequence to arrive at a functional enhancer. Orkin teaches SEQ ID NO: 254 encompasses the +55 region of the BCL11A enhancer (para. [0103] and Fig. 10). Orkin teaches the sequences comprises two matches to the consensus binding site for GATA-1 transcription factor (claim 2). Orkin teaches to further refine the area required for enhancer activity in the +55 region, a series of TALEN pairs were made to create mutations across this stretch of DNA (para. [0258]). Orkin teaches the TALENs were introduced into CD34+ cells, then the cells were induced to differentiate into erythroid cells (para. [0259]). The cells described by Orkin comprise chromosomes encoding instant SEQ ID NO: 5, the chromosome reads as an expression cassette.
Regarding claim 5, Orkin teaches the enhancer region was found within intron 2 of the BCL11A gene, and three areas of DNAseI hypersensitivity (often indicative of a chromatin state that is associated with regulatory potential) in intron 2 were identified (para. [0013]). Orkin teaches these three areas were identified as “+62, “+58 and “+55” in accordance with the distance in kilobases from the transcription start site of BCL11A (para. [0013]). Therefore, the region of the chromosome corresponding to the BCL11A gene comprises three different enhancer regions, +62, +58, and +55. Orkin teaches the sequence, SEQ ID NO: 254, comprises the +55 enhancer region and the other two enhancer regions would necessarily be present.
Regarding claims 6 and 8-9, Orkin teaches in example 2, following TALEN treatment, the deletions of regions within the +58 and +55 BCL11A DNAseI hypersensitive site resulted in an increase in the relative levels of gamma globin (γ-globin) expression (para. [0252]). The γ-globin discussed by Orkin reads as expressing a therapeutic agent (claim 6). The expression of γ-globin (claim 9) reads as the sequence encodes a therapeutic agent comprises a globin gene (claim 8).
Regarding claims 10, 16, and 18-19, Orkin teaches methods of altering gene expression in BCL11A and/or a globin gene in a cell, wherein gene expression is altered in a hematopoietic stem cell (claims 16 and 18), CD34+ cell (claim 19) (para. [0036] and [0051]). Orkin teaches the TALENs used were designed to create deletions in human hematopoietic stem and progenitor cells (HSPCs) (para. [0096]). Therefore, it is understood that the globin gene would be operably linked to a human erythroid promoter (claim 10).
Regarding claim 30, Orkin does not disclose instant SEQ ID NO: 1, however, this is a known sequence encompassed by the sequence for the human PPARA gene, as evidenced by NCBI (see alignment below), which has been mapped to human chromosome 22, as evidenced by Sher (Abstract and Fig. 2). The CD34+ cell of Orkin would have necessarily comprised human chromosome 22 and the chromosome reads as an expression cassette. Therefore, Orkin teaches the limitations of the claim to include instant SEQ ID NO: 1 with 100% sequence identity.
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Thus, the reference anticipates the subject matter of claims 1-2, 5-6, 8-10, 16, 18-19, and 29-30.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 3-4 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Orkin et al. (US 2015/0132269 A1, published 14 May 2015).
This is a new rejection necessitated by Applicant’s amendments to the claims.
Orkin anticipates the subject matter of claims 1-2, 5-6, 8-10, 16, 18-19, and 29-30, and thus, also render them obvious.
Regarding claims 3 and 4, Orkin does not teach wherein the expression cassette comprises multiple copies of the enhancer element (claim 3) or wherein the two copies are of the same enhancer element (claim 4).
However, it would have been obvious to one of ordinary skill in the art to utilize two copies of the same enhancer elements of Orkin with a reasonable expectation of success because Orkin teaches is exploring methods for increased globin production in CD34+ cells. A person of ordinary skilled in the art would have been motivated to utilize two copies of the same enhancer elements because MPEP § 2144.06(II) states, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). Therefore, it would have been obvious to utilize two copies of the same enhancer elements of Orkin because multiple copies of the same enhancer element has the potential to provide an additive or synergistic effect which could increase protein expression. Additionally, multiple copies of the same enhancer element would increase the number of binding sites for erythroid-specific transcription factors, such as GATA1, which are required for proper globin expression.
Regarding claim 32, Orkin teaches transgenic HSC/PC cells include transgenes encoding a human gene (para. [0035]). Orkin teaches the transgene is integrated into a selected locus into a stem cell, such as induced pluripotent stem cell (iPSC) or a hematopoietic stem cell (HSC) (para. [0035]).
Therefore, it would have been obvious to one of ordinary skill in the art to apply the teachings of Orkin to an iPSC with a reasonable expectation of success because Orkin teaches examples of both modified HSC and iPSCs. One would be motivated to utilize the iPSC because iPSCs is a well-known cell model for genetic research and have the capacity for an almost unlimited expansion, are amenable to genetic engineering, and have been widely applied to model human development and diseases, perform drug screening, and develop cell therapies.
Additionally, it would have been obvious to one of ordinary skill in the art to utilize an iPSC with a reasonable expectation of success because substitution of one known element for another known element, the elements having equivalent effect, is considered to be obvious, absent a showing that the result of the substitution yields more than predictable results. See MPEP 2143(I). Since iPSCs and HSCs would be equally capable of comprising an expression cassette as they are both capable and regularly utilized for transgenic expression.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claims 11, 13, 15, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Orkin et al. (US 2015/0132269 A1, published 14 May 2015) as applied to claims 1-6, 8-10, 16, 18-19, 29-30, and 32 above, and further in view of Ryu et al. (WO2018/009506, published 11 January 2018, of record).
This is a new rejection necessitated by Applicant’s amendments to the claims.
Orkin anticipates the subject matter of claims 1-2, 5-6, 8-10, 16, 18-19, and 29-30, and thus, also render them obvious.
Regarding claim 11, Orkin does not teach a vector comprising the expression cassette of claim 1, wherein the vector is a retroviral or lentiviral vector.
Ryu teaches a human GATA-1 erythroid specific enhancer sequence which is contained in a DNA construct (Abstract). Ryu teaches the disclosed DNA construct can be a cloning vector, expression vector, or expression cassette (para. [0009]). Ryu teaches erythroid-specific enhancers BCL11A +58 enhancer, GATA-1 enhancer, and HS40 enhancer, in two different orientations, were analyzed in combination with the glycophorin A promoter or Ankyrin promoter (para. [0018]). Ryu teaches this analysis indicated human GATA1 enhancer and BCL11A +58 erythroid specific enhancer provided the best enhancement of expression (para. [0018]). Ryu teaches the nucleotide coding sequence of interest is a nucleotide encoding a polypeptide which provides a therapeutic function for the treatment of a hemoglobinopathy (para. [0024]). Ryu teaches the nucleotide sequence coding the sequence of interest encodes a globin gene, such as α-globin, β-globin, γ-globin, or δ-globin (para. [0024]). Ryu teaches utilization of an erythroid-specific enhancer in combination with the glycophorin A promoter (a human erythroid promoter) to increase promoter strength without affecting lineage expression (para. [0018]). Ryu teaches the expression vector includes the erythroid lineage-specific promoter from glycophorin A operably linked to the nucleotide coding sequence of interest (para. [0011]). Ryu teaches the gene therapy vector is a retroviral vector or a lentiviral vector, since lentiviral vectors are capable of providing efficient delivery, integration and long-term expression of transgenes into non-dividing cels both in vitro and in vivo (para. [0031]).
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the enhancer region sequence disclosed by Orkin with the vector of Ryu with a reasonable expectation of success because both references teach methods of modifying production of globin genes by utilizing regions of the erythroid-specific enhancers found in the BCL11A gene. One would have been motivated to utilize the enhancer region sequence disclosed by Orkin with the vector of Ryu because Ryu teaches cell suitable for transduction and administration in the gene therapy methods include hematopoietic stem cells (HSCs) and Orkin also teaches modifying expression of globin proteins in HSCs.
Regarding claim 13, Ryu teaches erythroid-specific enhancers BCL11A +58 enhancer, GATA-1 enhancer, and HS40 enhancer, in two different orientations, were analyzed in combination with the glycophorin A promoter (a promoter) or Ankyrin promoter (para. [0018]). Ryu teaches the expression vector includes the erythroid lineage-specific promoter from glycophorin A operably linked to the nucleotide coding sequence of interest (para. [0011]). Ryu teaches the nucleotide coding sequence of interest is a nucleotide encoding a polypeptide that provides a therapeutic function for the treatment of a hemoglobinopathy (a therapeutic gene) (para. [0024]). Additionally, Ryu teaches the expression cassette may further include other DNA sequences, such as enhancers, UTRs, Kozak sequences, polyadenylation signals, additional restriction enzyme sites, and multiple cloning sites (para. [0011]).
Regarding claim 15, Ryu teaches lentiviral vectors comprising a CMV promoter
(Fig. 1 and para. [0006]).
Regarding claim 21, Ryu teaches the formulations or compositions disclosed are suitable for the delivery of viral vector including retroviral vectors (para. [0042]). Ryu teaches methods for preventing or treating a hematopoietic disorder by administering to a subject in need of treatment an effective amount of the disclosed DNA construct or viral vector (para. [0042], pp. 23-24). This reads as a pharmaceutical composition.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter: claim 31 requires a cell comprising the expression cassette of claim 1 wherein the enhancer consists of the nucleotide sequence set forth in one of SEQ ID NO: 1 or 3. While the enhancer sequences comprising SEQ ID NO: 1 and 3 are known, a cell comprising an expression cassette consisting of SEQ ID NO: 1 or 3 are not known in the art.
Claims 33 and 35 depend from claim 31, thus, also include allowable subject matter.
Claims 31, 33, and 35 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Claims 1-6, 8-11, 13, 15-16, 18-19, 21, 29-30, and 32 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NICHOLAS A. HUMPHRIES whose telephone number is (703)756-5556. The examiner can normally be reached Monday - Friday, 7:30am - 4:30 pm.
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/N.A.H./Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
