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 Objections
Claim 5 is objected to because of the following informalities: in line 2, “comprising” should be “comprises”. Appropriate correction is required.
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.
Issues Relevant to Both Written Description and Enablement Presented Once for Brevity
1) Scope of the Claims
The claims are drawn to methods of using chimeric proteins for effecting radioprotection, mitigating radiation injury, and treating acute radiation syndrome. The chimeric proteins have two components: 1) a targeting domain comprising a human annexin 5 or variants thereof, and 2) an activator domain comprising an insulin-like growth factor (IGF-1) and/or neuregulin (NRG) or variants thereof. The term “variant” is not limited by the number or type of structural changes to the annexin 5, IGF-1, or NRG. However, the term is limited by the functional requirement that the annexin variant be capable of targeting, the IGF-1 and NRG variants be capable of activating, and the chimeric protein be capable of effecting radioprotection, mitigating radiation injury, and treating acute radiation syndrome.
2) Actual reduction to practice/Working examples
The instant specification includes Example 4: mice were exposed to whole body irradiation and subjected to the treatment with a single IGF1-AnxV chimeric protein (scp776) or placebo, resulting in:
- improved survival (7 death/28 mice) in the scp776 treatment group compared to control (10/28);
- a significant improvement in maintenance of body weight in the scp776 treatment group;
- a decrease in clinical signs of disease in the in the scp776 treatment group; and
- a marginal trend towards higher severity grades for abnormal findings of macroscopic intestinal damage in control animals.
There is no reduction to practice of a variant of the IGF1-AnxV chimeric protein or of any chimeric comprising NRG as the activator.
3) Predictability in the art
The prior art of Antipov et al. (US 2017/0096469 A1; hereafter “Antipov”) discloses the chimeric proteins of the present invention, for use in promoting tissue regeneration or survival in patients suffering from e.g. kidney injury resulting from radiation among an exhaustive list of further disorders ([0440]). The examples in Antipov show that spc776 and spc757 variants preferentially target damaged cardiomyocytes in vitro, while further variants decrease hypoxia-induced apoptosis in human cardiomyocytes and/or kidney proximal tubule epithelial cells in vitro in a dose dependent manner, and reduce infarct size in a mouse model. Antipov does not mention any radioprotective effect of the variants.
4) Guidance in the specification/Structure-function correlation
The specification does not describe a general correlation between structure and function for the claimed genus. The role of each of the amino acids of IGF1 and NRG on radioprotection and annexin V on targeting are not described. As a result, it is impossible to predict, based on the specification, how changing any position will affect the claimed function.
Claims 1-8, 10-14, and 16-21 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.
The reduction to practice in the specification, which is limited to a single IGF1-AnxV chimeric protein is not representative of the full genus which includes variants as well as chimeric proteins wherein the activator is NRG. Furthermore, the lack of predictability in the prior art and the lack of structure-function correlation in the specification mean that the specification fails to describe the distinguishing characteristics of the genus. One of ordinary skill in the art would not know which of the countless chimeric proteins that meet the structural requirements of the claims would also be able to perform the complicated claimed functions. For these reasons, the skilled artisan would not reasonably conclude that the inventor(s), at the time the application was filed, had possession of the full scope of the claimed invention.
Claims 1-8, 10-14, and 16-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating acute radiation syndrome with the chimeric protein of claim 22 does not reasonably provide enablement for the treatment with any other chimeric proteins. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
To comply with the enablement requirements of 35 U.S.C. §112, first paragraph, a specification must adequately teach how to make and how to use a claimed invention throughout its scope, without undue experimentation. Plant Genetic Systems N.V. v. DeKalb Genetics Corp., 315 F.3d 1335, 1339, 65 USPQ2d 1452, 1455 (Fed. Cir. 2003). There are a variety of factors which may be considered in determining whether a disclosure would require undue experimentation. These factors include: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Factors (2)-(8) are discussed above.
The scope of the claimed compositions and therapeutic indications are extremely broad relative to the narrow reduction to practice in the specification. That fact combined with the level of unpredictability and complexity in the art, the relative skill in the art, and the lack of specific guidance in the specification, poses an undue burden of experimentation on one of ordinary skill in the art seeking to practice the claimed methods. The specification is an invitation to undertake a research program to identify additional compositions that could be used to carry out different embodiments of the claims. As such, the specification fails to meet the enablement provision of 35 U.S.C. 112(a).
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Antipov et al. (US 2017/0096469 A1; hereafter “Antipov”).
Claim interpretation: BRI of a subject in need of radioprotection includes subjects exposed to the sun, which is all human subjects.
Rejection: Antipov teaches methods of promoting tissue regeneration or survival in a subject, the method comprising (a) providing a bi-specific protein having (1) an activator domain, wherein the activator domain comprises a variant of IGF-1 and (2) a targeting domain, wherein the targeting domain comprises annexin A5 or variant thereof; and (b) administering in a patient in need thereof a therapeutically effective amount of the bi-specific protein whereby the Annexin A5 or variant thereof targets the bi-specific fusion protein to a first cell of the tissue, wherein the cell expresses phosphatidylserine on the outer leaflet of the plasma membrane, and whereby upon exposure of the IGF-1 variant to a IGF-1 receptor at the surface of a second cell, the IGF-1 variant specifically activates the IGF-1 receptor of so as to promote tissue regeneration ([0051]).
Antipov teaches that the subjects in need thereof include those suffering from a podocyte-related disease or disorder can be due radiation([0440]). These subjects are human subjects and are therefore continuously exposed to radiation from the sun, from which they need protection.
Antipov teaches that the composition comprising the bi-specific fusion protein is administered to a mammal (e.g., a human) continuously for 1, 2, 3, or 4 hours; 1, 2, 3, or 4 times a day; every other day or every third, fourth, fifth, or sixth day; 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times a week; biweekly; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 times a month; bimonthly; 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times every six months; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 times a year; or biannually ([0449]). Because humans are continuously exposed to radiation from the sun and in need of protection therefrom, each administration schedule taught in the prior art falls within the claimed range of timing.
MPEP § 2112.02(II) states: [W]hen the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978)
In the instant case, the claim recites a method of administering a chimeric protein comprising annexin 5 and IGF-1 to a subject in need of radioprotection and/or mitigation from radiation injury. The result of the claimed method, as expressed in the preamble of the claims is radioprotection and/or mitigation of radiation injury. The prior art teaches a method of administering a chimeric protein comprising annexin 5 and IGF-1 to subjects exposed to the sun but is silent as to the effect of radioprotection and/or mitigation of radiation injury. Because the prior art teaches all of the same active method steps as the claim, that is administering the same exact structure, to the same patients, in the same manner, the claimed effect of radioprotection and/or mitigation of radiation injury is inherent to the prior art method. The inventors have found a new property of radioprotection and/or mitigation of radiation injury and such a discovery does not constitute a new use.
Therefore, Antipov anticipates claims 1-3.
Allowable Subject Matter
Claim 22 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following claims drafted by the examiner and considered to distinguish patentably over the art of record in this application, are presented to applicant for consideration:
Cancel claims 1-3.
4. (Currently Amended) A method of treating acute radiation syndrome (ARS), the method comprising:
administering a composition comprising a therapeutically effective amount of a chimeric protein to a subject in need thereof,
wherein the chimeric protein comprises a targeting domain comprising human annexin 5 (AnxV) or variant thereof comprising a substitution at a position corresponding to C316 and optionally one or more substitutions at a position corresponding to R63, K70, K101, E138, D139, or N160, and an activator domain comprising insulin-like growth factor (IGF-1)comprising one or more substitutions at a position corresponding to E3, Y24, Y31, or Y60, and
wherein the composition is administered to the subject within 1 to 72 days after radiation exposure.
5. (Currently amended) The method of claim 4, wherein the chimeric protein further comprises[[ing]] a peptide, wherein the peptide extends the half-life of the chimeric protein.
Cancel claims 10-11.
The following is a statement of reasons for the indication of allowable subject matter: the closest prior art of Antipov does not teach nor suggest the treatment of acute radiation syndrome with the claimed chimeric proteins. Therefore, the proposed claims are novel and unobvious over the prior art.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA M MARCHETTI BRADLEY whose telephone number is (571)272-9044. The examiner can normally be reached Monday-Friday, 8:30 am - 5 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko G Garyu can be reached at (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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CHRISTINA M MARCHETTI BRADLEY
Primary Examiner
Art Unit 1654
/CHRISTINA M MARCHETTI BRADLEY/Primary Examiner, Art Unit 1654
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