DETAILED ACTION
The present application is being examined under the pre-AIA first to invent provisions. Claims 1-20 are pending.
This office action is in response to claims filed 12/2/2022.
This application is a divisional application of U.S. Serial Number 16/573,389 filed September 17, 2019, now U.S. Patent 11,542,493, which is a divisional of U.S. Serial Number 15/816,083 filed November 17, 2017, now U.S. Patent 10,472,619, which is a divisional application of U.S. Serial Number 14/647,547 filed 5/27/2015, now U.S. Patent No. 9,822,355 issued on November 21, 2017, which is a 35 U.S.C. 371 National Stage Application of International Application No. PCT/US2013/072236 filed on November 27, 2013, which designates the United States, and which claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 61/730,323 filed November 27, 2012, of U.S. Provisional Application No. 61/730,369 filed November 27, 2012, of U.S. Provisional Application No. 61/776,144 filed March 11, 2013, and of U.S. Provisional Application No. 61/889,174 filed October 10, 2013.
The presently claimed subject matter is first disclosed in its entirety in provisional application 61/776,144 and hence the effective filing date of the claims is 3/11/2013.
Information Disclosure Statement
Information Disclosure Statements filed 12/2/2022, 1/17/2024, 6/28/2024, 11/7/23024, 3/12/2025 and 5/23/2025 have been identified and the documents considered. The signed and initialed PTO Form 1449 has been mailed with this action. Initials indicate that the document has been considered even if the reference is lined through. In the case that only an English abstract was identified, this is indicated.
Claim Objections
Claims 1, 2, 6, 11 and 12 are objected to because of the following informalities: in claim 2, “ex vivo” should be italicized. This is true of claim 12.
Claim 6 uses DHSs as an abbreviation for DNAse hypersensitive sites, wherein “the first occurrence of DHS” should be spelled out as “DNAse hypersensitive sites” and thereafter the term DHS used.
Appropriate correction is required.
Claim 2 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 1. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). In this case, the method is recited as if in vitro as the cells are provided, introduced with the endonuclease or vector encoding and thereafter the cells administered to the mammal. As it appears by all measures to be in vitro it is the same as that recited in claim 2 as ex vivo.
Claim 12 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 11. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP 608.01(m). In this case, the method is recited as if in vitro as the cells are provided, introduced with the endonuclease or vector encoding and thereafter the cells administered to the mammal. As it appears by all measures to be in vitro it is the same as that recited in claim 12 as ex vivo.
As it is unclear on the face of the claims whether there is any difference in the methods if they are performed in vitro or ex vivo, the rejection above is made. However, in the case, there is no indication that the method will differ based upon the intended use. In the case that there is, below is provided a rejection under 35 USC 112, 4th.
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 1-20 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. The dependent claims are included in the rejection because they fail to address or clarify the basis of the rejection as discussed in detail for the independent claims.
Claims 1 and 12 are unclear as the method in part b) states that the fetal hg expression is increased in the mammal relative to expression prior to contacting. However, at this point the cells are only contacted with the endonuclease and there is no impact of the cell on the mammal and hence it is not clear how one would know the impact of the at least one modification.
Claims 2-4 recite the limitation "the isolated human hematopoietic progenitor" in claim 1. There is insufficient antecedent basis for this limitation in the claim. The claims only refer to a provided hematopoietic progenitor cells or hematopoietic stem cells.
Claims 12-14 recite the limitation "the isolated human hematopoietic progenitor" in claim 11. There is insufficient antecedent basis for this limitation in the claim. The claims only refer to a provided hematopoietic progenitor cells or hematopoietic stem cells.
Claims 5 recites the limitation "the at least one genetic modification" in claim 4. There is insufficient antecedent basis for this limitation in the claim as there are two references to at least one genetic modification, one in claim 1 and one in claim 4 and it is nto clear to which claim 5 references.
Claims 15 recites the limitation "the at least one genetic modification" in claim 14. There is insufficient antecedent basis for this limitation in the claim as there are two references to at least one genetic modification, one in claim 11 and one in claim 14 and it is not clear to which claim 5 references. This leads to issues of contradiction between the independent claims which starts with an isolated hematopoietic progenitor cell wherein a vector or RNA encoding a DNA endonuclease is introduced into the cell. The endonuclease cleaves the isolated cell within chromosome 2 between positions 60,716,189 and 60,728,612 in DHS sites +62, +58 or +55 to reduce the expression of mRNA or portion for BCL11A. However, claims 4-10 and 14-20 recite that this starting cell i.e. the cell prior to introduction of the vector or RNA encoding the endonuclease is genetically modified and with a deletion in either the entire of 60,716,189 and 60,728,612 or a part which disrupts one of +62, +58 or +55.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2 and 12 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. It is unclear if there is a difference between methods of producing the cells in vitro or ex vivo. However, should there be a distinction, that means claim 2 and 12 do not fall within the scope of claim 1 and 11. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112, first paragraph
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.
Claims 1-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims are drawn to a method of producing a genetically modified hematopoietic progenitor cell.
Claim Rejections - 35 USC § 112, first paragraph
The following is a quotation of the first paragraph of 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- 20 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for producing an in vitro method for increasing fetal hemoglobin expression by deleting +50.4-+60/4 with TALENS so directed in hematopoietic cells, does not reasonably provide enablement for any other embodiment. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the patent coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is not based on a single factor but is rather a conclusion reached by weighing many factors (See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter, 1986) and In re Wands, 8USPQ2d 1400 (Fed. Cir. 1988); these factors include the following:
1) Nature of invention. The instant claims are drawn to cell therapy for treatment of any hemoglobinopathy.
2) Scope of the invention. The scope of the invention is extremely broad in that the source of the hematopoietic cell is any, the disorder any, the at least one genetic modification any and the vector any. The claims lack enablement for the full scope of the claims for reasons below but also lack adequate description for the entirety of the claims. The relationship of enablement with the requirement for written description is acknowledged by the MPEP wherein one cannot use what one cannot envision.
3) Number of working examples and guidance. The specification teaches formation of hematopoietic cells from PBMCs from healthy donors. DNAse hypersensitive sites were identified at +62, +58 and 55 to reduce BCL11A, The +55, +58, and +62 DHSs deletions removed binding sites to the enhancer sequence allowing for reactivation of fetal hemoglobin by reducing BCL11A expression. A single deletion is manufacture with TALEN and the impact on BCL11A expression as well as on adult and embryonic is shown (see Figure 5). The level of fetal expression was never tested in subjects with the cell.
4) State of the art. Hemoglobinopathies are inherited blood disorders Steinberg (AM J Hematology, 2022, pages 676-678) in a recent review states that
Cell-based therapies inducing about 40% fetal hemoglobin (HbF), or aHbF-like hemoglobin in most erythrocytes, can—at least in the short-term—effect a cure or near-cure of β hemoglobinopathies, which are humankind's most common Mendelian diseases.
The common disorders such as sickle cell disease comprising a point mutation in the normal b-globin gene (HBB) and thalassemia comprising hundreds of different HBB mutations wherein HbF abrogates the impact of both.
Post filing art, (Demirci et al, Cell Stem Cell, 2025, pages 209–226) details manifestation of the method of transplanting cells into primate models and the impact. The method details the CRISPR sgRNAs as well as means to manipulate and achieve high g-globin expression (Demirci, see page 211, col 2).
5) Unpredictability of the art. The issues with the claims lie in the fact that they are not only broadly claimed but inadequately supported by the disclosure as well as the art at the time of filing. The disclosure itself considers its results exploratory and states,
[[0378]] Ultimately a better understanding of the causal regulatory elements and associated regulatory networks underlying traits could identify novel therapeutic targets. The erythroid enhancer of BCL11A could itself constitute a favorable target for therapeutic genome editing in that ablation could impede BCL11A expression in erythroid precursors with resultant HbF derepression while preserving BCL11A expression in non-erythroid lineages.
In its nascent state, the missing elements from the art must be detailed in the disclosure. However, there is no exemplification of the method from which these details can be derived. Though not controlling, the lack of working examples, is, nevertheless, a factor to be considered in a case involving both physiological activity and an undeveloped art. When a patent applicant chooses to forego exemplification and bases utility on broad terminology and general allegations, he runs the risk that unless one with ordinary skill in the art would accept the allegations as obviously valid and correct, the examiner may, properly, ask for evidence to substantiate them. Ex parte Sudilovsky, 21 USPQ2d 1702, 1705 (BPAI 1991); In re Novak, 134 USPA 335 (CCPA 1962); In re Fouche, 169 USPQ 429 (CCPA 1971).
First, is the cell source. More generally, for cell therapy, cells must be allogeneic or autologous. However, even limited it thus, Demirci et al details issue with both. The desire to develop autologous cells to avoid the lack of appropriate donors but even this approach post filing is complicated by unpredictability (see page 211, col 1 Demirci). As well and as set forth above claims 2-4 and 12-14 indicate the starting cell comprises a genetic modification. However, the specification does not describe this starting cell with a genetic modification. Rather, the deletion in all or part of the DHS region is the created from the DNA endonuclease. In fact, the disclosure describes as a starting cell a non-genetically modified hematopoietic cell that which means that the DHS region is intact and therefore able to be targeted by the endonuclease.
Secondly, the DNA targeting endonuclease is by nature able to cleave the genomic DNA. The claim simply require at least one genetic modification thereto such that fetal hemoglobin expression is increased. However, the disclosure teaches that one or more DHS site must be removed and hence, the at least one genic modification must be a deletion. The only exemplified such deletion is called D50.4-60.6. This deletion alone is analyzed and impact of ex vivo effects on isolated cells shown.
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But, the impact of this modification for in vivo use is not provided. Demirci et al find that initial studies varied which indicates a lack of predictability (see Demirci, page 220, col 1)
Finally, the claim requires in one case introduction of a vector “carrying” the coding sequence of the DNA endonuclease. This vector must express the endonuclease for impact and yet there is no expression control sequence to mediate this effect.
While the results presented in the art do not necessarily preclude Applicant's hypothesis, they certainly fail to support it. Consequently, the prior art (and post-filing art) when combined with the lack of any disclosed direct experimental test of Applicant's hypothesis, shows that one of skill in the art at the time the invention was made would have had no basis to reasonably predict or conclude the claimed invention would succeed. There is no evidence that the specification offers a solution to the problem set forth in the specification. Though not controlling, the lack of working examples, is, nevertheless, a factor to be considered in a case involving both physiological activity and an undeveloped art. When a patent applicant chooses to forego exemplification and bases utility on broad terminology and general allegations, he runs the risk that unless one with ordinary skill in the art would accept the allegations as obviously valid and correct, the PTO may, properly, ask for evidence to substantiate them. Ex parte Sudilovsky, 21 USPQ2d 1702, 1705 (BPAI 1991); In re Novak, 134 USPA 335 (CCPA 1962); In re Fouche, 169 USPQ 429 (CCPA 1971). IN essence applicants propose a method but leave the details up to one practicing the invention.
6) Undue experimentation. Claiming the invention broadly to fully protect the invention causes additional enablement issues. The PTO WD Guidelines assert that a single species may be sufficient to enable the claimed genus, but that a “representative” number of species is required. How many species are representative of the claimed genus can be assessed using the Wands factors for undue experimentation. To analyze claims for enablement, the Examiner will first construe the claim terms. Claim terms are defined in view of the specification and understanding in the art. The scope of the claim is also construed. Enablement is assessed for the full scope of the claims. Features of the invention described in the application as “critical” or “necessary” will be required in the claims. Preferred or exemplified embodiments are not essential to the claims. Inoperable embodiments, generally excluded by claim language, may be permitted, unless the Examiner asserts undue experimentation would be required to make and use operable embodiments of the claimed invention.
The claims have been evaluated in light of the art at the time of filing and found not to be commensurate in scope with the specification. MPEP 2164.05 teaches, “However, the examiner should carefully compare the steps, materials, and conditions used in the experiments of the declaration with those disclosed in the application to make sure that they are commensurate in scope; i.e., that the experiments used the guidance in the specification as filed and what was well known to one of skill in the art. Such a showing also must be commensurate with the scope of the claimed invention, i.e., must bear a reasonable correlation to the scope of the claimed invention. The invention recites use of a broad group of sequence. Given the unpredictability of the art, the poorly developed state of the art with regard to predicting the structural/ functional characteristics of antagonists, the lack of adequate working examples and the lack of guidance provided by applicants, the skilled artisan would have to have conducted undue, unpredictable experimentation to practice the claimed invention.”
Conclusion
Given that the instant claims are a result of a restriction requirement and the instant application is a divisional of parent application 16/573,389, the safe harbor protection under 35 U.S.C. § 121 applies.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIA MARVICH whose telephone number is (571)272-0774. The examiner can normally be reached on 8 am - 5 pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria Leavitt can be reached on 571-272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MARIA MARVICH/
Primary Examiner, Art Unit 1633
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