DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This office action is in response to an amendment filed 2/24/2026.
Claims 1-4, 6-8, 16 and 17 are pending.
This application is a divisional application of U.S. Patent Application No. 15/545,159, filed July 20, 2017, now U.S. Patent 11,611,632 which is a §371 application of PCT/US2016/014269, filed January 21, 2016, which claims priority to U.S. Provisional application no. 62/105,829, filed on January 21, 2015.
Response to Amendments
Applicants have clarified the reference noted as missing in the IDS filed 3/22/2022 was present and provided a copy. However, a replacement IDS was not provided so the IDS filed 3/22/2022 is resubmitted herein corrected.
The Amendment to the disclosure is sufficient to overcome the objection. The rejection under 35 USC 112, first has been overcome in part. The issues not addressed are underlined. Applicants have not addressed these in the response.
The arguments are sufficient to overcome the rejection under 35 USC 103.
New rejections necessitated by applicants amendment are identified below.
Claim Objections
Claim 1 is objected to because of the following informalities: for simplicity and consistency in claim structure once the abbreviations are set forth as in the first part of claim 1, the abbreviations should be used (in the second part of claim 1). Respelling out the abbreviations complicates the claims. Meanwhile, claim 3 abbreviates Ldb1 without the full spelling. Appropriate correction is required.
Claim Rejections - 35 USC § 112, second paragraph
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.
Claim 1 is 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. This is a new rejection necessitated by applicants’ amendment.
Claim 1 recites the limitation "the promoter" in claim 1, line 30. There is insufficient antecedent basis for this limitation in the claim. The claim requires “at least one promoter” and claim 27 does not clarify if it is all or only one and if one which one.
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 1-4, 6-8, 16 and 17 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for a method of treating thalassemia or sickle cell anemia in a subject, the method comprising administering autologous CD34+ erythrocytes to the subject wherein the erythrocytes are produced by isolating erythrocyte progenitor cells from the subject and infecting the cells with a lentivirus comprising in the 5' to 3' direction: a 5' long terminal repeat (LTR), a sequence that is the reverse complement of a sequence encoding modified adult human beta-globin comprising a bT87Q mutation (B-globinM) comprising a first intron (intron 1) between exon 1 and exon 2, and a second intron (intron 2) between exon 2 and exon 3 of said B-globinM sequence, wherein intron 2 comprises 851 nucleotides of human B-globinM intron 2 sequence under the control of the at least one promoter and linked to said first polyadenylation signal, a globin gene locus control region (LCR), a self-inactivating 3' LTR comprising an ankyrin insulator element (Ank), a Woodchuck Post-Regulatory Element (WPRE), and said second polyadenylation signal and further differentiating the infected progenitor cells into the erythrocytes (prior to administration) wherein the control viral vector is human B-globinM comprising intron 2 with 476 nucleotides, 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. This rejection is maintained however amended based upon applicants’ amendments.
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 a gene therapy method comprising delivering human b-globin to an individual with the goal of inducing expression of b-globin in erythrocytes.
2) Scope of the invention. The scope of the invention has been modified to a narrower breadth. However, these issue remain, the cells are differentiated into erythrocytes prior to administration to the subject. As well, the claim requires that the WPRE does not integrate into a target genome but the description of this element is simply that it is placed outside of the integrating portion of the vector. There is no other configuration. As well, SEQ ID NO:3 (subject matter of the previous scope) only demonstrated improved results with an intron 2 with 851 nucleotides.
Two claims recite processes without steps that are not supported in their full breadth by the disclosure. The first is the subsequent differentiation of the progenitor cells once introduced into the subject. Secondly, claim 7 recites an outcome with out steps. To the contrary, the scope establishes that the progenitor cells are differentiated prior to administration to the subject into erythrocytes. As to claim 7, the method results in treatment wherein the expression of the B-globinM can only lead to increased B-globinM based on the disclosure.
3) Number of working examples and guidance. The specification teaches in example 1-6 the construction of lentivirus expressing a fusion zinc finger and Ldb1 transcription factor and its effect in sickle erythroblasts in vitro. This structure binds the g-globin promoters to reactivate HbF, reduce sickle globin levels, down-regulate SOX6 and KLF1.
As to the claimed invention, little discussion is had. The diagram below provides the only details of how the components might be arranged. However, the examples do not describe how they might be used to the effect one might expect in vivo. The in vitro effects are that
This Example demonstrates that introducing the lentiviral vector ALS10 into CD34+ cells from β0/0 phenotype samples, and thus the most severe thalassemic specimens, results in statistically significantly elevated levels of HbA produced by erythrocytes derived from the modified CD34+ cells. The elevation in HbA is relative to a previously describe construct, which is used in this Example as a comparison control (AnkT9W, from Breda et al, Plos One, 2012), which did not include a complete intron 2. Thus, when compared to the previously described construct, ALS10 showed significant and unexpected improvement, as demonstrated by the results depicted in FIG. 12.
The constructs provided are below. The results limited to in vitro.
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4) State of the art. The invention is directed towards treatment with b-globin. This gene is related to only thalassemia and sickle cell disease (see abstract, Locatelli). The art teaches gene therapy approaches to treat b-thalassemia with a lentivector expressing bT87Q was not successful enough for therapeutic effects and demonstrated the inability to translate pre-clinical top clinical results (Dong et al, page 5-6, IDS filed 5/24/2022).
Therapeutic HbβT87Q LentiGlobin, however, only accounted for one-third of the total Hb, with endogenous HbE and HbF making up the rest. Without the additive effect of these endogenous Hbs, this first trial might not have been a success. This suggests that we not only need a predictive in vitro model with which to evaluate potential trial patients, but better vectors that can achieve higher therapeutic Hb expression.
5) Unpredictability of the art. As a first issue, the WPRE is configured such that the WPRE does not integrate into a target genome. What configuration of the WPRE is necessary is not provided for in the disclosure. In this case, there are specific elements referenced but the claims reference these structures wherein the means to configure is not provided except to use wild type WPRE.
Secondly, the differentiation of the cells from progenitor cells to erythrocytes is not demonstrated except in vitro. If there are steps that can ensure that this happens in the subject and the expression of the B-globinM can ensue such that the subject is treated they are not embodied in the disclosure.
6) Undue experimentation. The physiological art is recognized as unpredictable. (MPEP 2164.03.) In cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved. In this case, the nucleotide is broadly stated as being administered with broad and non-descript steps for an outcome that is not guaranteed given the in vitro results limited to use of SEQ ID NO:3. Hence, it is the art acknowledged lack of correlation in combination with the complexity of this art and the scope of the steps that makes the lack of relevant correlation important. Therefore, in vitro have allowed proof of principle issues to be established. In patent prosecution, this is relevant wherein the ability to establish a correlation is necessary. 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
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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 8 am - 5 pm.
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/MARIA MARVICH/Primary Examiner, Art Unit 1634
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