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 Group I in the reply filed on 10/23/2025 is acknowledged. The traversal is on the ground(s) that the groups share a special technical feature because the technical feature of claim 1 is not taught by the cited art (WO 2012/150326). Applicants assertion is convincing regarding Group III (claims 11-13) and these claims are thus rejoined in Group I.
This is not found persuasive regarding Group II because the methods of Group II do not provide any active method steps for obtaining the recited cells with the insertion of the nucleic acid sequence at the specific site in chromosome 17, i.e. a special technical feature of claim 1. Further, Group II recites a special technical feature, a selection marker gene, that is not found in the nucleic acid of Group I/claim 1. Group II remains restricted from Group I because the Groups do not share the special technical feature of an exogenous nucleic acid comprising a selection marker gene.
The requirement is still deemed proper and is therefore made FINAL.
Claim 6 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 timely traversed the restriction (election) requirement in the reply filed on 10/23/2025.
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 1-5, 7-15 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.
Ther claims are drawn to modified human stem cells, and methods of using such, comprising an exogenous nucleic acid sequence encoding a fusion protein of cytochrome P450 2B6 of SEQ ID NO: 1 and an NADPH-cytochrome P450 reductase of SEQ ID NO: 2, and variants or fragments of such with as little as 80% sequence identity to SEQ ID NOs 1 and 2. The fusion protein must comprise specific amino acid residues at positions 114V, 199M and 477W, with no other limitations placed on the variants or fragments. Considering substitution variants alone, this encompasses mutations at up to 97 residues in SEQ ID NO: 1 at any of the 488 positions not specifically recited above and up to 124 mutations at any of the 621 positions of SEQ ID NO: 2.
However the factors to be considered in making the determination as to whether one skilled in the art would recognize that the applicant was in possession of the claimed invention as a whole at the time of filing include:
a. Actual reduction to practice;
b. Disclosure of drawings or structural chemical formulas;
c. Sufficient relevant identifying characteristics such as
i. Complete structure,
ii. Partial structure,
iii. Physical and/or chemical properties or
iv. Functional characteristics when coupled with a known or disclosed correlation between function and structure;
d. Method of making the claimed invention;
e. Level of skill and knowledge in the art and
f. Predictability in the art.
While all of these factors are considered, a sufficient number for a prima facie case are discussed as they relate to the issues mentioned above.
The claims broadly encompass a genus of fusion protein variants and fragments of SEQ ID NO: 1 (CYP2B6) with as little as 80% identity, so long as the mutation at positions 114V, 199M and 477W in SEQ ID NO: 1 are retained, wherein the variant CYP2B6 can be fused to any variant or fragment of SEQ ID NO: 2 with as little as 80% identity.
However the specification only discloses the reduction into practice of the polynucleotide sequence that encodes the amino acid sequence of SEQ ID NO: 1 fused to SEQ ID NO: 2 wherein the encoded fusion protein retains the ability to correctly localize to the microsomal membrane and maintain sufficient enzymatic activity for electron transfer. Applicants have not reduced into practice the claimed genus of fusion protein variants of SEQ ID NO: 1 (including 114V, 199M and 477W) and SEQ ID NO: 2 with 80% identity that retain the ability to correctly localize to the microsomal membrane and maintain sufficient enzymatic activity for electron transfer. The specification does not teach even a single sequence variant of SEQ ID NO: 1 that retains any activity. The specification does not describe where, in the protein sequence of SEQ ID NO: 1, the variations can be made while preserving the activity (e.g. to activate the effect of cyclophosphamide). Furthermore the specification does not teach variants of SEQ ID NO: 2, also comprising up to 20% variation, that retain sufficient enzymatic activity for electron transfer.
The specification does not teach what the structure of the genus of variant fusion proteins would look like or how these might differ from their natural counterparts. Thus one of skill in the art cannot predict which positions within SEQ ID NO: 1 or SEQ ID NO: 2 can be varied, or to which variant amino acid residue said position should be changed to, without disrupting the activity of the fusion protein. Therefore the specification lacks information regarding variants that retain sufficient enzymatic activity for electron transfer activity and retain the ability to activate the effect of cyclophosphamide.
The level of skill in the art is such that one of skill would not be able to identify without further testing which of the genus of variants discussed above are fusion proteins that retain the desired activity. Based on the lack of knowledge and predictability in the art, those skilled in the art would conclude that applicants were not in possession of the claimed genus of fusion proteins based on the disclosure of SEQ ID NO: 1 and SEQ ID NO: 2 alone.
Claims 11-13 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the application coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc. 8 USPQD2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is a conclusion reached by weighing several factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQQ2d 1400 (Fed. Cir. 1988) and include the following:
State of the prior art and level of predictability in the art: In spite of considerable interest in the use of human stem cells as cancer treatment, the art of record contains no description of methods of preventing cancer with human stem cells, or of treating cancer by administration of only human stem cells engineered to express the recited CYP2B6 fusion protein. In the examples, De Wasziers et al (US 20140127180 A1) teaches that tumor cells expressing the instantly recited CYP2B6 fusion protein were highly susceptible to administration of cyclophosphamide (CPA) in vivo. Amara et al (2014, of record) teach that in vivo administration murine neural stem cells expressing CYP2B6 rendered gliomas sensitive to CPA. Thus, the relevant art is silent with regard to treating cancer by administration of human stem cells engineered to express the recited CYP2B6 fusion protein without further administration of CPA, and is silent about prevention of cancer by administration of such cells even with administration of CPA. This clearly evidences that cancer treatment and prevention with human stem cells engineered to express the recited CYP2B6 fusion protein was at an early stage of development at the time of filing and that the skilled artisan would not know how to make and use without explicit guidance from the specification or significant empirical experimentation.
Amount of direction provided by the inventor and existence of working examples:
The specification lacks any working examples of the claimed methods of cancer treatment or prevention. The specification discloses well-known methods for the genetic manipulation of human stem cells and administration.
Although the specification suggests, in a prophetic manner, a method by which one might attempt to treat or prevent cancer with the claimed cells, there is no evidence that the method contemplated would actually produce a therapeutic result in cancer treatment, or to prevent cancer. Thus, in order to make and use the invention as claimed, the skilled artisan would have to further develop human stem cell therapy such that methods of preventing or treating cancer by administration of human stem cells engineered to express the recited CYP2B6 fusion protein could be performed
Nature of the invention and Breadth of the claims: The claims are directed to methods of preventing or treating cancer by administration of human stem cells engineered to express the recited CYP2B6 fusion protein, the properties of which have been outlined above. The claims are not limited to any particular cancer. Thus, the claimed methods encompass a divergent genus of methods to prevent or treat any cancer in any patient. As the claims encompass such a broad genus, it is incumbent upon the disclosure to set forth the manner and process of making and using human stem cells engineered to express the recited CYP2B6 fusion protein that is commensurate with the scope of protection sought.
Relative skill of those in the art and quantity of experimentation needed to make or use the invention: Although the level of skill in the art of manipulating human stem cells is high, the level of skill in the art of using such cells to prevent or treat cancer is low. One would not be able to prevent or treat cancer given no more than the teachings available at the time of filing without undue experimentation. The art of record does not provide a single working example of using the claimed human stem cells to treat or prevent cancer. Likewise, all of the teachings in the instant application are prophetic. Given the broad scope of the claims, the early developmental stage and the unpredictability of the art at the time of filing, making and using embodiments of the claimed invention would clearly require undue experimentation. Therefore, the claims are properly rejected under 35 USC 112, first paragraph, as lacking enablement.
Given the above analysis of the factors which the courts have determined are critical in determining whether a claimed invention is enabled, it must be considered that undue and excessive experimentation would have to be conducted by the skilled artisan in order to practice the claimed invention.
Conclusion
No claim is allowed.
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/MICHAEL D BURKHART/Primary Examiner, Art Unit 1638