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 with traverse of HBG1 and mobilized peripheral blood in the reply filed on May 19, 2026 is acknowledged. The traversal is on the ground that HBG1 and HBG1 are “nearly identical.”
However, upon further consideration, the Election of Species Requirement is withdrawn. Claims 1-19 will be examined in their entirety.
Information Disclosure Statement
The Information Disclosure Statement filed July 14, 2023 has been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
It is noted that the Sequence Listing Incorporation by Reference paragraph lists the size of the ASCII text file as 14,644 bytes, whereas the ASCII file itself lists the size as 15,727 bytes.
Specification
The use of the terms LONZA at paragraphs [0036] and [0040]; TALEN at paragraph [0059]; AUTOMACS at paragraph [0068]; X-VIVO at paragraph [0068] and Table 1; NUCLEOCUVETTE at paragraph [0070]; MISEQ at paragraph [0071]; FACSARIA at paragraphs [0074] and [0079]; PROMINENCE at paragraph [0077]; QUANTASOFT at paragraph [0080]; TAQMAN at paragraph [0081]; NEB NEXT at paragraph [0085]; and NEXTSEQ at paragraph [0085]; which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required: The specification, although noting that the claimed cells and compositions thereof can be used in therapy, there is no clear antecedent basis for the phrase “further comprising a pharmaceutically acceptable carrier.”
Claim Objections
Claims 1, 5-6, 8, 12, and 15-16 are objected to because of the following informalities:
At claim 1, line 1, “derived” should be changed to “obtained.”
At claim 5, line 1, “derived” should be changed to “obtained.”
At claim 6, line 1, “characterized in that” should be changed to “wherein.”
At claim 6, lines 2 and 3, each occurrence of “derived” should be changed to “obtained.”
At claim 8, line 1, “derived” should be changed to “obtained.”
At claim 12, line 1, “derived” should be changed to “obtained.”
At claim 15, line 1, the comma after composition should be deleted.
At claim 16, line 1, “derived” should be changed to “obtained.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
Claims 1-19 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.
Claim 1 recites the limitation “the promoter region” in line 4 There is insufficient antecedent basis for this limitation in the claim.
Claims 2-6 depend from claim 1, and are therefore included in this rejection.
Claim 2 recites the limitation “the proximal promoter sequence” in line 3. There is insufficient antecedent basis for this limitation in the claim. Further, it is not clear what the term “proximal” means. Is there a specific distance to or from the promoter that is required in order to be deemed “proximal”?
Claim 3 recites the limitation “the proximal promoter sequence” in line 2. There is insufficient antecedent basis for this limitation in the claim. Further, it is not clear what the term “proximal” means. Is there a specific distance to or from the promoter that is required in order to be deemed “proximal”?
Claim 4 recites the limitation “the erythroid lineage” in lines 2-3. There is insufficient antecedent basis for this limitation in the claim.
Claim 6 recites the limitation “the erythroid lineage” in line 3. There is insufficient antecedent basis for this limitation in the claim.
Claim 7 recites the limitation “the promoter region” in line 4. There is insufficient antecedent basis for this limitation in the claim.
Claims 8-14 depend from claim 7, and are therefore included in this rejection.
Claim 11 recites the limitation “the erythroid lineage” in line 3. There is insufficient antecedent basis for this limitation in the claim.
Claim 15 recites the limitation “the promoter region” in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 15 recites the limitation “the bulk population of cells” in line 3. There is insufficient antecedent basis for this limitation in the claim.
Claims 16-19 depend from claim 15, and are therefore included in these rejections.
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.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claims 1-19 are rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
The claims recites a cells and compositions the cells obtained from a subject having a hemoglobinopathy, comprising at least one synthetic allele of an HBG1 or HBG2 gene.
The instant specification recites a method of treating a subject which includes administering to the subject a composition of cells comprising at least one synthetic allele of an HBG1 or HBG1 gene (paragraph [0014]). Further, the instant specification provides that the cells and compositions of cells are useful in therapy, such as the treatment of hemoglobinopathies including anemia, beta-thalassemia, and sickle cell disease (paragraph [0027]). In addition, the claimed cells can be used for autologous stem cell therapy (paragraph [0093]).
Thus, claims 1-19 are deemed to encompass human cells and tissues, which are present or intended to be present in a human organism, and which is non-statutory subject matter. As such the recitation of the limitation “isolated” cell would be remedial. See 1077 Off. Gaz. Pat. Office 24 (April 21, 1987).
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.
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 1 and 4-19 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Cowan et al. (PCT Patent Application Publication No. WO 2017/191503, published November 9, 2017, and cited in the Information Disclosure Statement filed July 14, 2023).
Regarding claim 1, Cowan discloses cells obtained from a subject having a hemoglobinopathy, which includes sickle cell disease, thalassemias, and other hemoglobinpathies (paragraphs [00223]-[00224]). Cowan discloses that the HBG1 and HGB2 genes can be involved (paragraphs [00223]-[00225]). Cowan discloses that there is a T→C mutation in the regulatory factors of gamma globulin genes at position -175, which is interpreted as being in the promoter region of either the HBG1 or HBG2 genes (paragraph [00709]). Cowan discloses that chromosome 11 is the location for the T→C mutation at -175 of the HBG1 or HBG2 genes (paragraphs [0025].
Regarding claim 4, Cowan discloses that the cell can be a CD34+ cell or an erythroid lineage cell (paragraphs [0036]-[0040] and [00242]).
Regarding claim 5, Cowan discloses that the cell can be a bone marrow cell, a hematopoietic progenitor cell, or a CD34+ cell (paragraphs [0036]-[0040]).
Regarding claim 6, Cowan discloses that the cells express gamma-globin at a higher rate in edited cells than wild-type cells (i.e., cells lacking the synthetic allele) (paragraph [0038]).
Regarding claim 7, Cowan discloses that the cells express gamma-globin at a higher rate of at least 30% in edited cells than wild-type cells (i.e., cells lacking the synthetic allele) (paragraph [0038]).
Regarding claim 8, Cowan discloses bulk cells edited cells, which is interpreted as inclusion of cells obtained from subjects that do not carry the T→C mutation, but which can be edited (paragraph [00136] and Figures 30A-30C).
Regarding claim 9, Cowan discloses that the cells have at least 1 modified allele (paragraphs [00228] and [00242]).
Regarding claim 10, Cowan discloses that the cells have at least 1 modified allele, which encompasses an average of 1.0 modified alleles per cell (paragraphs [00228] and [00242]).
Regarding claim 11, Cowan discloses that the cell can be a CD34+ cell or an erythroid lineage cell (paragraphs [0036]-[0040] and [00242]).
Regarding claim 12, Cowan discloses that the cell can be a bone marrow cell, a hematopoietic progenitor cell, or a CD34+ cell (paragraphs [0036]-[0040]).
Regarding claims 13-14, Cowan discloses that the cells express gamma-globin at a higher rate of at least 30% in edited cells than wild-type cells (i.e., cells lacking the synthetic allele) (paragraphs [0038] and [00174]-[00175]).
Regarding claim 15, Cowan discloses upregulation of gamma-globin expression in erythrocytes differentiated from bulk edited CD34+ cells at a rate of at least 40% (paragraph [00136] and Figures 30A-30C).
Regarding claim 16, Cowan discloses bulk cells edited cells, which is interpreted as inclusion of cells obtained from subjects that do not carry the T→C mutation, but which can be edited (paragraph [00136] and Figures 30A-30C).
Regarding claim 17, Cowan discloses that the cell can be CD34+ cells (paragraphs [0036]-[0040]).
Regarding claim 18, Cowan discloses that the cells can be in a composition comprising a pharmaceutically acceptable carrier (paragraphs [00560]-[00562]).
Regarding claim 19, Cowan discloses sequencing the entire genome of corrected cells, such that populations of specific cells can be isolated prior to implantation (paragraph [00552]).
Cowan discloses each and every limitation of claims 1 and 4-19, and therefore Cowan anticipates claims 1 and 4-19.
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.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Cowan, as applied to claims 1 and 4-19 above, and in view of Gori et al. (U.S. Patent Application Publication No. 2020/0157515, published May 21, 2020 and claiming priority to U.S. Patent Application No. 16/569,336, filed September 12, 2019).
Cowan discloses cells and compositions of cells having a T→C mutation at position -175 of the promoter region of HBG1 or HBG2 genes.
Cowan fails to disclose a mutation relative to the sequence of instant SEQ ID NO: 12.
Regarding claim 2, Gori discloses genome editing systems for altering expression of HBG1 and HBG2 loci (abstract). Gori discloses that alterations in a target region can be targeted by a guide RNA comprising a targeting domain having a variety of sequences 5’ of the transcription site of the HBG1 and HBG2 genes, including SEQ ID NO: 558, which is identical to instant SEQ ID NO: 12 (Appendix I, SEQ ID NO: 558).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use Gori’s targeting domain, which is identical to SEQ ID NO: 12, to effect alterations in the HBG1 or HBG2 genes. One of ordinary skill in the art would have been motivated to include the mutation and resulting alterations in the HBG1 or HBG2 genes in order to provide for a higher level of fetal hemoglobin as desired.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Cowan, as applied to claims 1 and 4-19 above, and in view of Adair et al. (PCT Patent Application Publication No. 2020/118110, published June 11, 2020, filed December 5, 2019, and cited in the Information Disclosure Statement filed July 14, 2023).
Cowan discloses cells and compositions of cells having a T→C mutation at position -175 of the promoter region of HBG1 or HBG2 genes.
Cowan fails to disclose a T→C mutation at position 12 of the proximal promoter sequence.
Regarding claim 3, Adair discloses genetically modified cells (abstract). Adair discloses that genetically modified cells can be used to treat hemoglobinopathies (paragraph [0046]). Adair discloses that the allele can include a target at position 12 of the proximal promoter sequence and that the target at position 12 can be a -228 T→C mutation (paragraphs [044] and [081]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include the -228 T→C (at position 12 of the proximal promoter sequence) in order to provide additional allelic differences in gamma-globin expression. One of ordinary skill in the art would have been motivated to include the additional mutation in order to provide for a higher level of fetal hemoglobin as desired.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Skene et al. (13(5) Nature Protocols 1006-1019 (2018), and cited in the Information Disclosure Statement filed July 14, 2023) disclose an epigenomic profiling strategy called “cleavage under targets and release using nuclease (CUT&RUN),” which can be used for determining gene expression patterns (abstract and page 1006, column 1, first paragraph).
Coleman et al. (42 American Journal of Hematology 186-190 (1993), and cited in the Information Disclosure Statement filed July 14, 2023) disclose hereditary persistence of fetal hemoglobin (abstract). Coleman et al. disclose a T→C gamma-globin mutation at -175 of the promoter (abstract).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NANCY J LEITH whose telephone number is (313)446-4874. The examiner can normally be reached Monday - Thursday 8:00 AM - 6:30 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, NEIL HAMMELL can be reached at (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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NANCY J. LEITH
Primary Examiner
Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
Prosecution Insights