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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.
Claims 1, 7, 8, 19, 27, 29, 30, 82 and 83 are pending and under examination.
Applicant elected exogenous antigen and immunomodulator as species is acknowledged.
35 USC § 112(b) paragraph rejections withdrawn
The rejections of claims 1, 7, 8, 19, 27, 29, 30, 82 and 83 under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly are withdrawn in view of Applicant’s amendments to claim 1 and Applicant’s arguments.
35 USC § 102 rejections withdrawn
The rejections of claims 1, 7, 8, 19, 27, 29, 30, 82 and 83 under 35 U.S.C. 102(a1) as anticipated by WO 2012/149255 (IDS) are withdrawn in view of Applicant’s amendments to claim 1 and Applicant’s arguments.
35 USC § 112(a) paragraph rejections maintained
The rejection of claims 1, 7, 8, 19, 27, 29, 30, 82 and 83 for failing to comply with the enablement requirement are maintained.
Applicant argues that the instant application provides that repeated administration of antigen-specific immunotherapeutics can be affected without such broad immunosuppression. Applicant argues that with this discovery along with the teachings of the instant application, one of ordinary skill in the art would not only recognize that such a result was possible but also be able to determine and select protocols to achieve such a result. Applicant argues that the instant specification provides ample descriptions of what is meant by "immunosuppression" along with details and examples of assays, including KLH challenge assays, by which immunosuppression can be assessed. Applicant states that the Office is respectfully reminded that the instant specification defines "immunosuppression" as a (1) non-durable statistically-significant downregulation of an immune response as a result of repeated administration of an antigen-specific immunotherapeutic, or (2) the response of a non-human test subject to a KLH challenge T-cell dependent antibody response ELISA assay, assuming that KLH is not the antigen of interest, following at least one repeated administration of an antigen-specific immunotherapeutic, wherein the response is characterized as the KLH IgG titer (reported as EC50) changing from level of positive control to a titer (reported as EC50) equivalent to, or less than, 3 standard deviations above the mean negative control with same KLH dosing.
Applicant argues that the instant specification also provides what is meant by "protocol" along with methods by which they can be determined. Applicant argues that an ordinarily skilled person in the art reviewing the specification, which includes the foregoing teachings, would understand and be able to assess immunosuppression and to determine protocols that meet the desirable criteria of the claims without any undue or unreasonable experimentation.
Applicant further argues that working examples are provided, which demonstrate the assessment of immunosuppression as well as exemplary protocols. See specification as filed, for example, Examples 1 and 17-19. Applicant argues that it is important to note that these working examples demonstrate methods of repeated administration without immunosuppression for more than one antigen (e.g., ovalbumin (OVA) and KLH), for different modes of administration (e.g., subcutaneous, intravenous, intraperitoneal, and different combinations thereof) and even for different types of antigen-specific immunotherapeutics (e.g., synthetic nanocarriers comprising rapamycin (and antigen, e.g., OVA), methotrexate, and an OVA-ERY1 conjugate). Applicant argues that guidance and direction is provided in the instant specification that is more than reasonably correlated to the scope of the claims. Applicant argues that the disclosure of the instant specification goes beyond the methods of the claims, at least as working examples are provided for different types of antigen-specific immunotherapeutics beyond the synthetic nanocarriers of the claims. Applicant argues that these Examples demonstrate that repeated administration of an antigen-specific immunotherapeutic resulted in the reduction of immune responses in an antigen-specific manner and meeting the requirement of not inducing immunosuppression.
Applicant’s arguments have been considered but are not persuasive. As stated previously enablement requires that the specification teach those in the art to make and use the invention without undue experimentation. In re Wands, 8 USPQ2d 1400 (CA FC 1988). Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations. (Id.).
The specification discloses methods comprising determining a protocol for repeatedly administering an antigen-specific immunotherapeutic that does not result in immunosuppression in a subject. The claim recite method comprising repeatedly administering to a subject an antigen-specific immunotherapeutic according to a protocol. The claims do not recite a method comprising determining a protocol for repeatedly administering an antigen-specific immunotherapeutic that does not result in immunosuppression in a subject.
WO 2012/149255 teaches the method of the instant claims comprising repeatedly administering and antigen specific immunotherapy comprising the administration of an exogenous antigen and exogenous immunomodulator, together or separately, including the coupling of said antigen and immunomodulator to a polymeric synthetic nanocarrier, said method further discussing methods for determining protocols that were capable of inducing immunosuppression as well as protocols not capable of inducing immunosuppression (pages, 6, 25, 28, 40, 62, and 63).
Thus, both WO 2012/149255 and the present application teach methods comprising determining a protocol for repeatedly administering an antigen-specific immunotherapeutic that does not result in immunosuppression in a subject. The difference is that the purpose of WO 2012/149255 is to determine a protocol which induces immunosuppression. But by determining the protocol for inducing immunosuppression WO 2012/149255 would also determine which protocols do not induce immunosuppression.
The present claims are drawn to a method comprising repeatedly administering to a subject an antigen-specific immunotherapeutic according to a protocol, wherein the antigen-specific immunotherapeutic comprises an exogenous antigen and polymeric synthetic nanocarriers coupled to rapamycin or a rapamycin analog and wherein repeated administration of the antigen-specific immunotherapeutic according to the protocol does not result in immunosuppression in the subject. However, the specific protocol is not defined in the claims nor the specification. It appears that the claims are reciting a protocol to be determined in the future.
The specification discloses that when ovalbumin is administered to an experimental animal in combination with rapamycin enclosed within a PLGA nanocarrier reduced antibody titers to ovalbumin are seen while antibody titers to KLH remain elevated (Example 1). The PLGA nanoparticle with the rapamycin was made using a protocol recited at page 60, line 5 to page 61, line 3). It is not clear if the ovalbumin peptide is attached to the nanocarrier. The nanocarrier comprising rapamycin and the ovalbumin peptide (t2SVP) were presumably administered in footpads, the same location as the OVA and KLH peptides (page 65). But it is not clear if t2SVP were administered at the same exact location and at the same time as both the OVA and KLH peptides. It appears from Example 1 that the OVA peptide and KLH peptide were administered in different locations (OVA and CpG with 3 injections at d0, dl4 and d28 in the right front and hind footpads; KLH in the left front and hind footpads). It is not clear if the reduction in antibody production specific to OVA would occur if the administration of the OVA peptide occurred in a different location or at a different times. It is not clear where t2SVP was administered and on what days. In addition, the results of Example 1 disclose that there was immunosuppression in the response to OVA.
And as previous discussed it is not clear if the same results could be demonstrated with any exogenous antigen. Furthermore, it does not appear as if the rapamycin is coupled to the nanocarrier but enclosed within the nanocarrier.
MPEP 2164.08(b) states that
The presence of inoperative embodiments within the scope of a claim does not necessarily render a claim nonenabled. The standard is whether a skilled person could determine which embodiments that were conceived, but not yet made, would be inoperative or operative with expenditure of no more effort than is normally required in the art. Atlas Powder Co. v. E.I. du Pont de Nemours & Co., 750 F.2d 1569, 1577, 224 USPQ 409, 414 (Fed. Cir. 1984) (prophetic examples do not make the disclosure nonenabling).
Although, typically, inoperative embodiments are excluded by language in a claim (e.g., preamble), the scope of the claim may still not be enabled where undue experimentation is involved in determining those embodiments that are operable. A disclosure of a large number of operable embodiments and the identification of a single inoperative embodiment did not render a claim broader than the enabled scope because undue experimentation was not involved in determining those embodiments that were operable. In re Angstadt, 537 F.2d 498, 502-503, 190 USPQ 214, 218 (CCPA 1976). However, claims reading on significant numbers of inoperative embodiments would render claims nonenabled when the specification does not clearly identify the operative embodiments and undue experimentation is involved in determining those that are operative.
The specification discloses that in a preferred embodiment, non-durable statistically-significant downregulation means that the downregulation (treatment
arm measured against non-treatment arm) does not evidence a statistically-significant difference for longer than a week following the last repeated administration of the antigen-specific immunotherapeutic (page 19, lines 1 to 6). Various inventive compositions, methods, protocols, and dosages forms do not result in, or do not induce, immunosuppression (Id). Importantly, the specification discloses methods comprising determining a protocol for repeatedly administering an antigen-specific immunotherapeutic that does not result in immunosuppression in a subject. Thus, the generic limitation “protocol” recited in the claims is to be determined in future experiments.
It is noted that Fig 1 demonstrates that the response to the OVA peptide was immunosuppressed. Thus, administration of the antigen-specific immunotherapeutic does result in immunosuppression in the subject. The specification recites that the results in Fig. 1 show that, following repeated administration of an
antigen-specific immunotherapeutic, the titers against OVA are greatly affected by treatment with t2SVP (five left set of columns) but not the anti KLH titers. The specification only discloses the antibody response to one antigen, the KLH protein was not immunosuppressed.
In addition, the specification discloses that the OVA peptide was a 17 amino acid fragment of ovalbumin (page 65, line 27. It is unclear whether the KLH antigen was a peptide or the full length KLH protein. Thus, it is not clear whether the size of the antigen made any difference to whether or not there was immunosuppression in the subject. The peptide also appears to be enclosed along with the rapamycin within the nanocarrier (Example 1). It’s not clear if the same effect would occur if different administration modes were used for the OVA and KLH peptides as well as t2SVP. It is not clear whether it’s required that the exogenous be enclosed within the nanocarrier comprising rapamycin, attached to the nanocarrier or may be administered separately from the nanocarrier. It is not clear whether the exogenous antigen must be administered simultaneously with the nanocarrier. It is not clear whether nanocarriers comprising polymers other than PLGA and PLGA-PEG or nanocarrier of different sizes would function as claimed.
Also, given that the experimental animal was administered the OVA peptide and KLH protein along with an adjuvant to induce immune responses to the OVA peptide and KLH, it is not clear whether any localized or systemic immune response without an adjuvant would be affected by t2SVP, and whether the route of administration of t2SVP would affect the immune responses to the OVA peptide and KLH protein.
As discussed previously, the results from Figure 1 must present a showing of enablement which is commensurate in scope with the claims or at least as much of the claims as have been objected to In re Armbruster, 158 USPQ 152. Given the breadth of claim 1 it is not clear which of the numerous embodiments encompassed by the claims would not result in immunosuppression in the subject. As stated above, the issue is whether a skilled person could determine which embodiments that were conceived, but not yet made, would be inoperative or operative with expenditure of no more effort than is normally required in the art.
Given the disclosure of the specification and the teaching in the art that indicates the role of rapamycin of inducing antigen-specific immunosuppression, one skilled in the art could not predictably determine which experimental protocols using a nanocarrier couples to rapamycin would not result in immunosuppression in the subject.
Therefore, in view of the breadth of the claims, lack of guidance in the specification, and the state of the art, it would require undue experimentation for one skilled in the art to practice the invention as broadly claimed.
It is noted that Examples 17-19 concerned immunosuppression of immune responses with methotrexate using specific protocols.
In response to Applicant’s argument that Applicant argues that the instant specification also provides what is meant by "protocol" along with methods by which they can be determined, the claims are drawn to a method comprising repeatedly administering to a subject an antigen-specific immunotherapeutic according to a protocol, not a method for determining a protocol. As MPEP 2164.08(b) recites “claims reading on significant numbers of inoperative embodiments would render claims nonenabled when the specification does not clearly identify the operative embodiments and undue experimentation is involved in determining those that are operative”. As discussed above, given the numerable variables that must be taken into account, undue experimentation would be involved in determining which protocols involving the numerous variables would not result in immunosuppression in a subject.
ODP rejections maintained
The rejections of claims 1, 7, 8, 19, 27, 29, 30, 82 and 83 for obviousness-type double patenting as allegedly being unpatentable over claims of U.S. Patent No. 8,652,487; U.S. Patent No. 10,039,822; U.S. Patent No. 10,668,053; U.S. Patent No. 10,357,482; U.S. Patent No. 10,357,483; U.S. Patent No. 10,434,088; U.S. Patent No. 9,987,354; U.S. Patent No. 9,993,548; U.S. Patent No. 10,441,651; U.S. Patent No. 10,420,835; U.S. Patent No. 11,779,641 U.S. Patent Application No. 14/269,042; U.S. Patent Application No. 15/061,096;; U.S. Patent Application No. 16/438,147; U.S. Patent Application No. 16/858,349; U.S. Patent Application No. 17 /690,437; U.S. Patent Application No. 18/063,610; U.S. Patent Application No. 18/064,211; U.S. Patent Application No. 18/177,714; and U.S. Patent Application No. 18/330,345 are maintained.
Applicants state that in view of the non-allowed state of the application, they propose that these rejections be deferred until allowable subject matter has been identified and maintains the right to subsequently address these rejections if necessary.
In response, the rejections are maintained.
Summary
Claims 1, 7, 8, 19, 27, 29, 30, 82 and 83 stand rejected
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/MARK HALVORSON/ Primary Examiner, Art Unit 1646