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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 8/10/2026 has been entered.
Claims 1, 3, 4, 7, 8, 16 and 18-28 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.
Information Disclosure Statement
An IDS filed 8/10/2026 has been identified and the document considered. The signed and initialed PTO Form 1449 has been mailed with this action.
Response to Amendments
Applicants amendments are sufficient to overcome the previous objections. As well, the rejections under 35 USC 112, b have bene overcome by amendment.
Claim Objections
Claims 16, 19, 23, 24 and 28 are objected to because of the following informalities: when referring to SEQ ID NO:s i.e. claims 16, 23 and 28, it is proper to refer to –the nucleotide sequence of SEQ ID NO:-- as SEQ ID NO:s are placeholders and not sequences themselves this indicates the extent of coverage.
In claims 19 and 24, 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 claims 19 and 24). Respelling out the abbreviations complicates the claims. Appropriate correction is required.
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, 3, 4, 7, 8, 16 and 18 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) thus configured to not be integrated into the target genome+, and said second polyadenylation signal and further differentiating the infected progenitor cells into the erythrocytes (prior to administration) wherein the differentiated erythrocytes in the subject produce more B-globinM 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 for reasons underlined above.
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.
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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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.
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, 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.”
Response to Arguments
Relevant to the rejection remaining, applicants argue that the methods of in vivo differentiation are supported by Kanter et al which teaches introducing CD34+ cells comprising a lentiviral vector encoding B-globinM wherein the cells engrafted and produced hemoglobin. As set forth in the scope of enablement that the cells can engraft and produce hemoglobin is not the actual dispute. However, it is noted that the rejection does establish that it is B-globinM that is produced from the procedure and not fetal or adult hemoglobin. What is rejected is the explicit recitation of in vivo differentiation. Differentiation is notably performed ex vivo. The methods require careful calibration of growth conditions and factors wherein even these methods show low production rates and requirements that are not available in vivo (see abstract and page 247 col 1-2 of Uchida et al, Molecular Therapy, Methods & Clinical Development, pages 247-256). Repopulating cells is not a predictable art (see Anurogo et al International J of Molecular Sciences, 2021, pages 1-27) and the reference provided does not teach to the alternative. It teaches that CD34+ cells transplanted can produce hemoglobin. This is not in contest.
Conclusion
Claims 19-28 are objected to or depdentn on an objected to claim but are otherwise allowable.
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/MARIA MARVICH/Primary Examiner, Art Unit 1634
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