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 .
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 92, 99, 101, 102 , 105 -107, 110, 113-119 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.
Applicants claim fusion proteins comprising portions of SEQ ID NO: 6, variants thereof, nucleotides encoding said proteins, cells comprising the fusion proteins and methods of making and using the cells. Applicants disclose a single amino acid sequence (SEQ ID NO: 6) and DNA sequence (SEQ ID NO: 7). The claims read on a broad genus of fusion proteins and variants (and the other inventions based on the fusion protein), such as any amino acid sequence with 85% homology to the recited portions of SEQ ID NO: 6.
The written description requirement for a genus may be satisfied by sufficient description of a representative number of species by actual reduction to practice or by disclosure of relevant identifying characteristics, i.e. structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between structure and function, or by a combination of such identifying characteristics, sufficient to show that applicant was in possession of the claimed invention. The court and the Board have repeatedly held (Amgen Inc. v. Chugai Pharmaceutical Co. Ltd.,18 USPQ2d 1016 (CA FC, 1991); Fiers v. Revel, 25 USPQ2d 1601 (CA FC 1993); Fiddes v. Baird, 30 USPQ2d 1481 (BPAI 1993) and Regents of the Univ. Calif. v. Eli Lilly & Co., 43 USPQ2d 1398 (CA FC, 1997)) that an adequate written description of a nucleic acid requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it, irrespective of the complexity or simplicity of the method; what is required is a description of the nucleic acid itself. It is not sufficient to define a fusion protein solely by its principal biological property, because disclosure of no more than that, as in the instant case, is simply a wish to know the identity of any fusion property with that biological property. Naming a type of material generically known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material. When one is unable to envision the detailed constitution of a complex chemical compound having a particular function, such as a nucleic acid or protein, so as to distinguish it from other materials, as well as a method for obtaining it, conception has not been achieved until reduction to practice has occurred, i.e., until after the fusion protein has been isolated or sequences. Thus, claiming all proteins or DNA’s that achieve a result without defining what means will do so is not in compliance with the description requirement. Rather, it is an attempt to preempt the future before it has arrived.
The specification does not describe a single species of protein that encodes a functional fusion protein (SEQ ID NO: 6 is a fusion between IL-15 and IL-15Ra) that is not either 100% identical to SEQ ID NO: 6.
While one of skill in the art can readily envision numerable species of IL-15/IL-15Ra fusion protein sequences that are at least a given % identity to a reference sequence and that encode a polypeptide at least a given % identity to a recited reference amino acid sequence, one cannot envision which of these also encode a IL-15/IL-15Ra fusion protein with a specified activity.
In the instant case, applicants only disclose the amino acid sequence of SEQ ID NO: 6, and the associated nucleic acid sequence of SEQ ID NO: 7. Neither applicants nor the prior art disclose other IL-15/IL-15Ra fusion proteins as claimed. Applicants are claiming other forms of IL-15/IL-15Ra fusion protein and variants by function only, without a correlation between structure and function. The diversity of the IL-15/IL-15Ra fusion protein and DNA sequences claimed, along with the lack of disclosure regarding other IL-15/IL-15Ra fusion protein variants, would require the skilled artisan to conclude that the single species presented by the applicants is not sufficient to describe the claimed genus.
The specification also provides no teachings on what amino acid sequence modifications, e.g. insertions, deletions and substitutions, would be permissible in a variant polypeptide that would improve or at least would not interfere with the biological activity or structural features necessary for the biological activity and stability of the IL-15/IL-15Ra fusion protein. It is not possible to even guess at the amino acid residues which are critical to its structure or function based on sequence conservation.
In Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991), the court ruled that a claim to a large genus of possible genetic sequences encoding a protein with a particular function that needs to be determined subsequent to the construction of the genetic sequences may not find sufficient support under 35 USC 112, 1st para., if only a few of the sequences that meet the functional limitations of the claim are disclosed and if undue experimentation would be required of one skilled in the art for determining other genetic sequences embraced by the claim. This is the case here, where specification discloses only one putative functional amino acid sequence, SEQ ID NO: 6, for a polypeptide having the necessary activity, and provides no guidance on determining which polypeptide variants of SEQ ID NO: 6 that would have an activity of SEQ ID NO: 6.
Claim 92 only requires 351 residues of the functional species that is disclosed (SEQ ID NO: 6 is 422 residues). An 85% identical sequence could substitute any amino acid residue into any of the 53 sites that are permissible to be changed and retain the 85% identity to the recited SEQ ID NO: 6 portions. Further, relative to the disclosed SEQ ID NO: 6, the fusion protein of claim 92 permits the deletion of up to 69 residues found in the full length SEQ ID NO: 6 (a further reduction in homology of 16% relative to the full length polypeptide).
Claim 117 is 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 cells engineered to express Interleukin 15, the art of record contains no description of methods of treating any given disease or condition using cells engineered to express only a fusion of IL-15 and IL-15Ra. For example US Patent No. 8,507,222 (of record) teaches construction of cells expressing separate fusion proteins, one with IL-15 and another with IL-15Ra. Although these engineered cells could stimulate lymphocytes, they were not demonstrated to treat any disease or condition in vivo. This clearly evidences that using IL-15 fusion proteins in engineered cells to treat disease was at an early stage of development at the time of filing and that the skilled artisan would not know how to treat any given disease or condition using the claimed cells without explicit guidance from the specification or significant empirical experimentation.
Amount of direction provided by the inventor and existence of working examples:
In the working examples, the specification teaches production of CAR T cells that have activity for treating tumor models in vivo. The specification also discloses well-known methods for making such cells.
Although the specification suggests that the claimed cells could be used to treat diseases other than tumors or cancer, there is no evidence that the methods contemplated would actually produce an efficacious result. Thus, in order to make the invention as claimed, the skilled artisan would have to further develop the methods of making and using the engineered cells such that they were capable of functioning in a wide variety of cell types and could function therapeutically in a broad range of potential diseases
Nature of the invention and Breadth of the claims: The claims are directed to methods of treating a disease or condition ion a human subject, the properties of which have been outlined above. The claims are not limited to any particular disease, condition, or cell type. Thus, the claimed methods encompass a divergent genus that depends upon the disease and cell type in which the therapy is sought. As the claims encompass a wide variety of species of potential diseases or conditions, it is incumbent upon the disclosure to set forth the manner and process of making and using such engineered cells 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 making IL-15/ IL-15Ra engineered cells is high, the level of skill in the art of using such cells to treat a disease is low. One would not be able to make and use such cells 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 the claimed cells that is operative in the treatment of a disease. Likewise, all of the teachings in the instant application are specifically directed to treating a single type of disease (cancer) with cells that comprise additional therapeutic proteins (CAR), with additional prophetic statements suggesting how the technology might be further developed for application in the treatment of other diseases. Given the broad scope of the claims, the early developmental stage and the unpredictability of the art at the time of filing, making operative 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.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 92, 98, 99, 101, 102, 105-119 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 7,10, 11, 15-21, 23, 25 of U.S. Patent No. 9,629,877. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant fusion proteins, nucleic acids, cells and methods comprise or encode the same IL-15/IL-15RA fusion protein as recited in the ‘877 claims, which recite the instant SEQ ID NO: 6.
Claims 92, 98, 99, 101, 102, 105-119 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-8, , 10-14, 17-20 of U.S. Patent No. 11,786,582. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant fusion proteins, nucleic acids, cells and methods comprise or encode the same IL-15/IL-15RA fusion protein as recited in the ‘582 claims, which recite the instant SEQ ID NO: 6.
Conclusion
No claim is allowed.
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/MICHAEL D BURKHART/Primary Examiner, Art Unit 1638