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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 49-51, 58, 60-69, 71, 72, and 75 are pending.
Claims 61-63 had been withdrawn.
Claims 49-51, 58, 60, 64-69, 71, 72 and 75 are under examination.
35 USC § 112(a) rejections maintained
The rejections of claims 49-51, 58, 60, 64-69, 71, 72 and 75 under 35 U.S.C. 112(a) as failing to comply with the written description requirement for new matter are maintained.
The specification as filed does not disclose the limitation “at least two of five top ranked neoantigenic epitopes”.
The rejections of claims 49-51, 58, 60, 64-69, 71, 72 and 75 under 35 U.S.C. 112(a) as failing to comply with the written description requirement are maintained.
A.
Applicant argues that the application as filed demonstrates that the Applicant had possession of the claimed invention. Applicant directs the Office to at least paragraphs [0009], [0011], [0014], [0015], [0018], [0020], [0091], [0104], [0108]-[0111], [0117], [0274], [0275], [0292], [0295] and [0296] ; Examples 6-7, 16, 17, and 19-21; and Figures 8, 12, 14, 17 and 18 of the application as-filed, which demonstrate that Applicant had possession at the time of invention of a method of treating a subject diagnosed as having a neoplasia with a subject-specific composition by identifying and ranking neo-antigenic epitopes, and administering the subject-specific composition comprising APCs comprising the neo-antigenic epitopes, or T cells stimulated with the APCs.
(A)(1).
Applicant argues that the Specification describes a method that identifies and ranks, exemplary species of the genus of neo-antigenic epitopes to be processed and presented by APCs. Applicant states that the claim requires an active step of ranking neoantigenic epitopes, and this ranking directly affects whether the identified neo-epitopes are included in the claimed subject specific composition, based on affinity and mutation type. Applicant states that these limitations specify that the epitopes are not any random epitopes, but are required by the claim to fall within the ranking criteria (i)-(v), which are explicitly recited in Example 7 and Figure 8 of the specification, as further discussed below in (1 )(b ). 25 Accordingly, one of skill in the art would recognize that the ranking method selects only a fraction of neo-antigenic epitopes with neoORF or
missense mutations that further meet the binding affinities recited in the claims.
Applicant states that Pending independent claim 49 is drawn to a method of treating by administering a subject-specific compositions comprising antigen presenting cells comprising neo-antigenic epitopes, or T cells stimulated by the APCs, ranking neo-antigenic epitopes encoded by the plurality of sequences comprising missense and/or neoORF mutations in an order of decreasing priority, and administering a subject-specific composition that comprises (A) antigen-presenting cells (APCs) comprising at
least two of five top ranked neo-antigenic epitopes encoded by the plurality of sequences comprising missense and/or neoORF mutations based on the ranking, or a polynucleotide encoding the at least two of five top ranked neo-antigenic epitopes or (B) T cells stimulated with the APCs of (A). Applicant argues that the ranking criteria therefore defines the "top-ranked" neo-antigenic epitopes, allowing a person of skill in the art to include at least two of five top ranked neo-antigenic epitopes in the claimed APCs.
Applicant argues that the specification as-filed shows the Applicant had possession of APCs comprising at least two neo-antigenic epitopes falling within the scope of the claimed methods. Applicant argues that the application as-filed shows many examples of neo-antigenic epitopes, or polynucleotides encoding such epitopes, that were identified by steps (a) and (b) recited in the claimed methods. Applicant argues that the genus of neo-antigenic epitopes has the following distinguishing
identifying characteristics: (I) comprises missense or neoORF mutations (structural characteristic); and (II) binds to an HLA of the subject with a predicted binding affinity that fall within ranking criteria (i)-(v) (structural characteristic). Applicant argues that the working examples of the specification as filed discloses numerous examples of neo-antigenic epitopes exhibiting the distinguishing identifying characteristics 1-11. Example 17 and Table 7 of the application as-filed shows 112 neo-antigenic epitopes comprising mis sense mutations and predicted binding scores of less than 500 nM that were identified from four different chronic lymphocytic leukemia (CLL) patients.27 Further, as described in Example 17, binding scores generated by HLA-peptide binding predictions were validated experimentally using a MHC I allele binding assay. Applicant argues that a majority (54.5%) of predicted epitopes were experimentally validated as binders to personal HLA alleles in vitro.
In addition, Applicant argues that Example 16 describes HLA-peptide binding affinities of known functionally derived immunogenic mutated epitopes across human cancers using NetMHCpan algorithm (see Tables 4 and 5). Applicant argues that
Table 6 shows that the numbers and affinity distributions of peptides predicted from 31
CLL cases with available HLA typing. Applicant also points to Example 21, which
discloses that numerous candidate epitopes were predicted across 13 different cancers, including mutant polypeptides with missense and neoORF mutations and HLA binding affinities that fall within criteria (i)-(iv) of the pending claims In Example 19, 25 neo-antigenic epitopes comprising missense mutations were identified by whole exome sequencing for a CLL patient 1. 30 Thirty neo-antigenic peptides from 13 mis sense mutations were predicted to bind to personal HLA (13 peptides with IC50<150; 17 peptides with IC50 150-500 nM). APCs were pulsed with neoantigen peptide pools and used to expand T cells, which were shown to be reactive with the neoantigenic peptides. Example 20 demonstrated APCs pulsed with neoantigen peptide pools from a second CLL patient resulted in T cells reactive to the neoantigenic peptides. Applicant argues that the application as filed discloses that exome sequencing data from 31 CLL
samples revealed that per case, a median of 22 epitopes were predicted to bind to personal HLA-A and -B alleles with IC50<500 nM originating from missense mutations. Approximately 75% and half (54.5%) of predicted epitopes with IC50<150 nM and 500 nM, respectively, were experimentally validated to bind to the patient's HLA alleles. Applicant argues that the predicted epitopes were used to pulse APCs which were capable of generating reactive T cells.
Applicant’s arguments have been considered but are not persuasive. The claims are drawn to method of treating a subject diagnosed as having a neoplasia with a
subject-specific composition, comprising:
(a) identifying a plurality of sequences comprising missense and/or neoORF mutations in the neoplasia, wherein identifying comprises sequencing a genome, transcriptome, or proteome of the neoplasia in the subject and sequencing a genome, proteome, or transcriptome of nonneoplastic cells from the subject; and
(b) ranking neo-antigenic epitopes encoded by the plurality of sequences comprising
missense and/or neoORF mutations in an order of decreasing priority, the order comprising:
(i) a neoORF epitope that binds to an HLA of the subject with a Kd of :S 500 nM
encoded by a sequence comprising a neoORF mutation,
(ii) an epitope that binds to an HLA of the subject with a Kd of :S 150 nM encoded by
a sequence comprising a missense mutation, wherein the native cognate epitope has a
Kd of 2: 1000 nM,
(iii) an epitope that binds to an HLA of the subject with a Kd of :S 150 nM encoded
by a sequence comprising a missense mutation, wherein the native cognate epitope
has a Kd of :S 150 nM,
(iv) a neoORF epitope that binds to an HLA of the subject with a Kd of> 500 nM
encoded by a sequence comprising a neoORF mutation,
(v) an epitope that binds to an HLA of the subject with a Kd of from greater than 150
nM to 500 nM encoded by a sequence comprising a missense mutation, wherein the
native cognate epitope has a Kd of from greater than 150 nM to 500 nM; and administering a subject-specific composition that comprises (A) antigen-presenting cells
(APCs) comprising at least two of five top ranked neoantigenic epitopes encoded by the plurality of sequences comprising missense and/or neoORF mutations based on the ranking, or a polynucleotide encoding the at least two of five top ranked neo-antigenic epitopes or (B) T cells stimulated with the APCs of (A).
It has been interpreted that the present claims require the ranking of peptides based on the criteria (b) (i)-(v). However, the specification does not disclose any specific ranking of epitopes nor the administration of the ranked peptides. Example 7 just indicates how peptides may be prioritized based on a number of criteria and cite Fig. 8. Fig.8 just indicates the groupings as present in the claims. However, the specification does not demonstrate any ranking of peptides or the treatment of a subject with neoplasia with the ranked peptides. Figure 8 just recites the groups (i)-(v).
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As discussed previously, possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. The court in In re Alonso (Fed. Cir. 2008) citing In re Enzo, Enzo, 323 F.3d at 969 stated that [F]or purposes of satisfying the written description requirement, it is not enough merely to disclose a method of making and identifying compounds capable of being used to practice the claimed invention. Like what was found in In Rochester, the Specification only disclose how to obtain possession of the genus of neoantigenic polypeptides that have been ranked in order of decreasing priority and producing and administering at least two of the top ranked neo-antigenic epitopes prioritized based on (i)-(v).
Applicant argues that the specification discloses peptides that fall within the groups (i)-(v). However, disclosing peptides that fall within the groups (i)-(v) is not the same as actually ranking the peptides and selecting peptides based on the rankings. If Applicant want to claim selecting peptides that fall within the groups (i)-(v), Applicant should amend the claim to recite selecting peptides that fall within the groups (i)-(v).
As stated by Applicant they have demonstrated that they found a correlation between the predicted affinity of a peptide to a specific MHC molecule and the actual binding of the peptide to the MHC molecule. Applicant has also demonstrated that pools of peptides were capable of inducing a T cell response. However, the specification disclose that approximately 5% of predicted peptides generated from missense mutations yielded detectable T cell responses (page 143, lines 19-20). Thus, the majority of combinations of two neo-antigenic epitopes would not elicit a T cell response.
Furthermore, as discussed previously, Sette teaches utilization of quantitative assays to measure the binding of antigenic peptides to MHC class I molecules and disclose that binding affinities of peptides to class I molecules. (Abstract; page 5591, 1st paragraph to page 5592, 1st paragraph). Sette disclosed that immunogenicity of the peptides correlated with the binding affinity of the peptides with the MHC molecule and found that an affinity threshold of approximately 500 nM determines the capacity of a peptide epitope to elicit a CTL response. (Id). Thus, it was already known that peptides with greater affinity to a specific MHC molecule would be more likely to elicit a T cell response.
The Court stated that “an adequate written description must contain enough information about the actual makeup of the claim products – a precise definition such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other material,” which may be present in “function “terminology “when the art has established a correlation between structure and function” (page 17, 1st paragraph). While knowledge of the anchor residues of particular peptides necessary to bind to a particular MHC molecule would give some information about the structure of the peptide, one could not identify the specific amino acid structure of a functional neoantigenic polypeptide based only on the missence or neoORF mutations in a neoplasia of a subject and the MHC molecule of the subject.
It has been interpreted that methods of treating a subject diagnosed as having a neoplasia with a subject-specific composition to be practical applications of the identification and ranking steps recited in the present claims. Thus, it has been interpreted that the neoantigenic polypeptides must be functional which means they must be immunogenic. While one of skill in the art would be able to identify specific peptides based on specific parameters using computer algorithms one would not know which of these neoantigenic polypeptides would be functional. As discussed above, the specification disclose that approximately 5% of predicted peptides generated from missense mutations yielded detectable T cell responses (page 143, lines 19-20).
In addition, it is noted that based on the findings of Sette, the neoantigen peptides characterized by falling within criteria (i)-(v) would encompass almost all possible functional peptides having missense and neoORF mutations capable of eliciting a T cell response. Thus, Applicant’s argument that the identified epitopes fall within criteria (i)-(v) is not relevant because the claim requires that the neo-antigenic epitopes are ranked in an order of decreasing priority based on the criteria (i)-(v). It is noted that the ranking limitation steps (i)–(v) were inserted into claim 1 to overcome previous art rejections. It does not appear that any of the listed neo-antigenic epitopes were ranked in an order of decreasing priority based on the criteria (i)-(v) in the specification.
(A)(1)(a).
Applicant argues that the neo-antigenic epitopes are identified from a plurality of
sequences comprising missense or neoORF mutations in the neoplasia that fall into each of ranking criteria (i)-(v). Applicant argues that a method comprising identifying a plurality of sequences comprising missense or neoORF mutations, ranking neo-antigenic epitopes encoded by the plurality of sequences by the ranking criteria (i)-(v) and administering antigen presenting cells (APCs) comprising one or more polypeptides comprising at least two neo-antigenic epitopes is not only reduced to practice in the
instant specification, but is also clearly and fully described in the instant specification such that a skilled artisan reading the application would have reasonably understood that the inventors had possession of the claimed invention
In response it is noted that the claims are drawn to a method of treating a subject diagnosed as having a neoplasia with a subject-specific composition not a method of identifying a plurality of sequences comprising missense or neoORF mutations in the neoplasia that are ranked according to the criteria (i)-(v). It has been interpreted that claims drawn to a method of treating a subject diagnosed as having a neoplasia with a subject-specific composition to be practical applications of the identifying and ranking steps recited in the present claims. Thus, it has been interpreted that the neo-antigenic epitopes must be functional which means they must be immunogenic. While one of skill in the art would be able to identify neo-antigenic epitopes based on specific parameters using computer algorithms one would not know which of these neo-antigenic epitopes would be functional. As discussed above, the specification disclose that approximately 5% of predicted peptides generated from missense mutations yielded detectable T cell responses (page 143, lines 19-20).
In response to Applicant’s argument that FIG. 8 is a table that shows the ranking assignments for different neo-antigenic mutations according to an exemplary embodiment of the invention, the claims are drawn to ranking neo-antigenic epitopes encoded by the plurality of sequences comprising missense or neoORF mutations sequences comprising the neo-antigenic mutations in an order of decreasing priority. Fig. 8 is just a general schematic for ranking the neo-antigenic peptides. The specification does not appear to include any ranking of the listed neo-antigenic polypeptides in an order of decreasing priority according to Figure 8. It is not sufficient that the peptides fall within the criteria (i)-(v). The claims require that the neo-antigenic peptides are ranked according to the criteria (i)-(v). It is noted that the ranking limitation steps (i) – (v) were inserted into claim 1 to overcome the previous art rejections. It does not appear that any of the neo-antigenic epitopes were ranked in an order of increasing priority based on the criteria (i)-(v) in the specification.
(A)(1)(b).
Applicant argues that the present disclosure provides adequate description by identifying the characteristics of neo-antigenic epitope that fall within the criteria of the claimed methods. Applicant argues that the specification as filed teaches identifying characteristics of the claimed methods such that a person of ordinary skill in the art would recognize APCs comprising neo-antigenic epitopes falling within the scope of the claimed methods. In this case, the epitopes falling within the scope of the claims must be identified according the following method: (b) ranking neo-antigenic epitopes encoded by the plurality of sequences comprising missense or neoORF mutations in an order of decreasing priority, the order comprising (i) through (v). Applicant argues that
together these limitations specify that the epitopes are not any random epitopes, but
are required by the claim to fall within the ranking criteria (i)-(v), which are explicitly recited in Example 7 and Figure 8 of the application specification. Applicant argues that a sufficient level of distinguishing identifying characteristics correlated with a specific functional characteristic are disclosed and claimed such that a skilled artisan is unlikely to be left in any doubt as to the genus of APCs comprising neo-antigenic epitopes identified by the claimed method.
Applicant’s argument has been considered but is not persuasive. As discussed previously, the claims are draw to a method of treating a subject diagnosed as having a neoplasia with a subject-specific composition not a method of identifying a plurality of sequences comprising missense or neoORF mutations in the neoplasia that are ranked according to the criteria (i)-(v). As discussed above, it has been interpreted that methods of treating a subject a composition comprising ranked neoantigenic polypeptides to be practical applications of identify and ranking steps recited in the present claims. Thus, it has been interpreted that the neoantigenic polypeptides must be functional which means they must be immunogenic. If the selected neoantigenic peptides were not immunogenic, the treating of a subject diagnosed as having a neoplasia with a subject-specific composition would not be a practical application of the identifying and ranking and selecting steps and the claims would not be directed to patentable subject matter. In addition, it is not sufficient that the peptides fall within the criteria (i)-(v). The claims require that the peptides are ranked according to the criteria (i)-(v). Furthermore, immunogenic peptides must be identified by their amino acid sequence, not by general characteristics that are applicable for almost any peptide. In addition, it was already known that the affinity of a particular peptide to a specific MC molecule was correlated to the immunogenicity of a particular peptide. However, this characteristic of a peptide does not tell one anything about the amino acid structure of an immunogenic peptide given that the vast majority of peptides are not immunogenic.
(A)(1)(c).
Applicant argues that according to paragraphs [0009], [0011] [0018], [0021], [0292] and [0295] a method comprising identifying and ranking neo-antigenic epitopes prioritized based on (i)-(v) and encoded by the plurality of sequences comprising missense or neoORF mutations based on the ranking, and administering APCs comprising one or more polypeptides comprising at least two neo-antigenic epitopes, or T cells stimulated by the APCs, is not only reduced to practice in the instant specification, but is also clearly and fully described in the instant specification such that a skilled artisan reading the application would have reasonably understood that the inventors had possession of the claimed method.
Applicant’s arguments have been considered but are not persuasive. The claims are drawn to a method of treating a subject diagnosed as having a neoplasia with a subject-specific neoplasia vaccine composition, comprising identifying a plurality of sequences comprising missense and/or neoORF mutations in the neoplasia, wherein identifying comprises sequencing a genome, transcriptome, or proteome of the neoplasia, ranking at least 20 neo-antigenic epitopes encoded by the plurality of sequences comprising missense and/or neoORF mutations sequences comprising the neo-antigenic mutations in an order of decreasing priority, the order comprising criteria (i)-(v) and (c) administering a subject-specific neoplasia vaccine composition that comprises APCs comprising one or more polypeptides comprising at least two of five top ranked neo-antigenic epitopes encoded by the plurality of sequences comprising missense and/or neoORF mutations based on the ranking, not a method of identifying and ranking neo-antigenic epitopes encoded by the plurality of sequences comprising missense or neoORF mutations sequences comprising the neo-antigenic mutations in an order of decreasing priority based on the criteria (i)-(v). It is noted that it appears that the only immunogenic peptides had the (iii) criteria. It is not clear how the inventors had possession of the production of neo-antigenic peptides based on the criteria (i)-(v) when the specification does not disclose the ranking of any of the listed peptides identified by their amino acid structure.
As discussed previously, a method of treating a subject diagnosed as having a neoplasia with a subject-specific neoplasia vaccine composition comprising neo-antigenic epitopes would require knowledge of the amino acid sequence of the neo-antigenic epitopes. Furthermore, as discussed above, it has been interpreted that methods of administering a subject-specific neoplasia vaccine composition that comprises APCs comprising at least two of five top ranked neo-antigenic epitopes are practical applications of the identifying and ranking steps recited in the present claims. Thus, it has been interpreted that the neoantigenic polypeptides must be functional which means they must be immunogenic. As discussed previously, the specification disclose that approximately 5% of predicted peptides generated from missense mutations yielded detectable T cell responses. Thus, it is unlikely that the vast majority of two epitopes would be immunogenic. Furthermore, as discussed previously, possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.
(A)(1)(d)
Applicant argues that according to paragraphs [0018], [0139] [0292], [0295], [0301], [0303], [0315], [0323] and [0337], a method comprising administering the subject-specific composition to the subject diagnosed as having neoplasia is clearly and fully described in the instant specification such that a skilled artisan reading the application would have reasonably understood that the inventors had possession of the claimed method.
In response, it is understood that methods for identifying peptides that may be used in the context of an MHC on an APC are well known in the art. The issue is whether the structure of the neo-antigenic epitopes to be administered in the context of the APC to treat a subject diagnosed as having a neoplasia are adequately described in the specification. As previously discussed, it has been interpreted that the neo-antigenic polypeptides must be functional which means they must be immunogenic. If the selected neoantigenic peptides were not immunogenic, the treating of a subject diagnosed as having a neoplasia with a subject-specific composition would not be a practical application of the identifying and ranking and selecting steps and the claims would not be directed to patentable subject matter. In addition, it is not sufficient that the peptides fall within the criteria (i)-(v). The claims require that the peptides are ranked according to the criteria (i)-(v). None of the listed peptides in the specification were ranked according to the criteria (i)-(v). Thus, the specification do not disclose the amino acid structure of any neo-antigenic peptides that have been ranked according to the criteria (i)-(v) and was shown to be antigenic.
(A)(1)(e)
Applicant argues that the APCs comprising neo-antigenic epitopes identified by the claim methods when administered to the subject would be expected to be immunogenic. Applicant agrees that in order for the APCs comprising neoantigen
peptides to treat a subject with a neoplasia the peptides must be immunogenic. Applicant argues that the specification as filed adequately discloses methods of
making and producing a subject-specific composition comprising APCs comprising at least two neo-antigenic epitopes that would be expected to be immunogenic. Applicant argues that the application as-filed contains disclosure that demonstrates that APCs comprising the neoantigenic epitopes that are identified and ranked via criteria (i)-(v), or T cells stimulated by the APCs, would reasonably be expected to be a suitable treatment to administer to cancer patients. Applicant argues that the application as-filed describes neo-antigenic polypeptides comprising neoORF or missense mutations that fall within criteria (i)-(v) of the claims are expressed in CLL tumors. As shown in Example 18 and Figure 12D, 80% of the 347 mutated genes (or 79% of the 180 mutations with predicted HLA-binding) were expressed at medium or high expression levels in CLL tumors, demonstrating that a CTL response to the identified neo-antigenic polypeptide would target the CLL tumor.
Applicant argues that their investigation revealed that patients exhibited a combination of missense and neoORFs mutations that should be prioritized when
selecting immunogenic polypeptides. Applicant argues that the immune microenvironment in post-allogeneic hematopoietic stem cell transplantation (HSCT) in a CLL patient was analyzed to determine whether an immune response against predicted polypeptides could develop in patients. Reconstitution of T cells from a healthy donor following HSCT can overcome endogenous immune defects of the host, and also allow for priming against leukemia cells in the host in vivo. Experimental validation of polypeptide predictions confirmed HLA binding for 14 of the neo-antigenic peptides. All 30 ranked neo-antigenic polypeptides for CLL patient 1 were selected for T
cell priming and stimulation studies, and were organized into 5 pools of 6 polypeptides/pool. T cells were tested for neo-antigen reactivity by expanding them using autologous APCs pulsed with the aforementioned neo-antigenic polypeptide pools. Reactivity in an IFN-y ELISPOT assay was detected against Pool 2, but not against control. Deconvolution of the pool revealed that two ranked neo-antigenic peptides, ALMS 1 and C6orf89, were shown to be immunogenic. Applicant argues that these studies demonstrate that APCs comprising neo-antigenic peptides identified by the claimed method, or T cells stimulated by the APCs, are a suitable treatment to administer to cancer patients. Example 20 discloses yet another CLL patient 2 where a neo-antigenic polypeptide was shown to be immunogenic. From this patient, 26 missense mutations were identified. 37 polypeptides were predicted to bind to personal HLA alleles, of which 18 polypeptides were experimentally validated (15 with IC50<150; 3 with IC50 150-500 nM). In Patient 2, the 18 ranked neo-antigenic polypeptides were selected for T cell priming and stimulation studies and were organized into 3 pools of 6
polypeptides/pool. As shown in Figure 17B, reactivity in an IFN-y ELISPOT assay was detected against Pool 1, but not against control. Deconvolution of the pool revealed that one ranked neoantigenic polypeptide, mut-FNDC3B, to be an immunogenic polypeptide and falling within the scope of category (iii) of the pending claims. Applicant states that they were able to identify epitopes generated by somatic mutations that elicited long-term T cell responses in multiple patients. Additionally, the specification as filed shows that T cell responses against CLL neoepitopes were long-lived. Specifically, about 5% of the peptides in this working example "of predicted peptides generated from missense mutations yielded detectable T cell responses." Applicant argue that the specification as filed not only discloses several examples of the subject-specific composition, but also shows that the claimed methods were applied successfully to CLL patients who developed clinically evident and durable remission associated with anti-tumor immune
responses following allogeneic-HSCT. Applicant argues that they successfully identified a genus of APCs comprising at least two neoantigenic epitopes, or polynucleotides encoding epitopes, having the distinguishing identifying characteristics of (I) comprising missense or neoORF mutations (structural characteristic); and (II) binding to an HLA of the subject with a predicted binding affinity that fall within ranking criteria (i)-(v) (structural characteristic), or T cells stimulated by the APCs. Applicant argues that APCs comprising at least two of five top ranked neo-antigenic epitopes as claimed process the polypeptides and present the neo-antigenic epitopes on the surface of the APC in complex with HLA.
Applicant arguments have been considered but are not persuasive. The issue is whether there is sufficient support for the genus of neo-antigenic epitopes that have been ranked based on (i)-(v) and were immunogenic. The specification disclose that approximately 5% of predicted peptides generated from missense mutations yielded detectable T cell responses (page 143, lines 19-20). Thus, the vast majority of the peptides listed in the specification would not be immunogenic. Although the immunogenicity of a peptide is correlated with its binding affinity to a specific MHC molecule, most of the peptides in the criteria (i)-(v) would likely not be immunogenic.
Claim 49 recites administering a subject-specific composition that comprises APCs comprising at least two of five top ranked neoantigenic epitopes. The specification does disclose the structure of 3 immunogenic neoantigenic peptides but in most cases the results were obtained using pools of 6 peptides, some pools of which did not result in any immunogenic peptides. As previously discussed, the amino acid structure of the peptides are required for the immunogenic peptides to be adequately described. The specification only appears to disclose how these neo-antigenic epitopes will be identified and ranked. It does not appear from the specification that any of the listed peptides were selected based on the claimed ranking system. The three immunogenic peptides, ALMS1, C6orf89 and FNDC3B appear to have IC50 of < 150 nm and had similar IC50 as the wild type peptide (Tables 9, 10). Thus, the specification does not appear to disclose the amino acid structure of any neo-antigenic peptides that were identified and ranked and capable of inducing an immune response in a subject diagnosed as having a neoplasia.
In response to Applicant’s argument that the application as-filed describes neo-antigenic polypeptides comprising neoORF or missense mutations that fall within criteria (i)-(v) of the claims are expressed in CLL tumors, the claims recite that the neo-antigenic peptides are ranked according to the criteria (i)-(v), not that the neo-antigenic polypeptides fall within the criteria (i)-(v). None of the listed peptides in the specification appear to be ranked according to the criteria (i)-(v). Thus, the specification does not disclose any neo-antigenic peptides that have been ranked according to the criteria (i)-(v) and was shown to be antigenic.
In response to Applicant’s argument that the application as-filed contains disclosure that demonstrates that APCs comprising the neoantigenic epitopes that are identified and ranked via criteria (i)-(v), or T cells stimulated by the APCs, would reasonably be expected to be a suitable treatment to administer to cancer patients, as previously discussed, possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features The specification does not appear to disclose any neo-antigenic peptides that have been ranked according to the criteria (i)-(v) and shown to be antigenic.
(A)(2)
Applicant argues that the exemplary APCs having the neo-antigenic epitope species identified and ranked described in the specification are representative of the genus and show a structure-function relationship. Applicant argues that the genus of neo-antigenic epitopes identified by the claimed method and processed and presented by the APCs of the subject-specific composition have several structural characteristics
(i.e. the distinguishing identifying characteristics of 1-11) that correlate to their function (i.e. their immunogenicity), and hence, their ability to elicit a tumor-specific immune response in a subject and thus be used to treat cancer. Applicant argues that the ability of these ranked neo-antigenic polypeptides to be presented by APCs and recognized and bound by cytolytic T cells in the context of the tumor can result in killing of the tumor. To trigger a T cell response, the cancer-specific peptides thus (i) must be presented to the cytolytic T cells in the context of a peptide:HLA complex on the surface
of APCs; and (ii) must be tumor specific and be recognized as "foreign" by the T cells. Applicant argues that the genus of neo-antigenic epitopes identified by the claimed method and processed and presented by APCs has the required structural characteristics (i.e. the distinguishing identifying characteristics of I-II) to elicit such a tumor-specific immune response.
Applicant first argues that each species within the genus of the neo-antigenic polypeptides identified and ranked by the claimed method, include a missense or neoORF mutation relative to the corresponding wild type peptides that are expressed in the non-cancer cells of the patient, and are thus tumor-specific and recognized as "foreign" by the immune system. Because the mutation property of the ranked
neo-antigenic polypeptides permits cytolytic T cells that recognize these mutated peptides to avoid immune tolerance, such T cells that are capable of being activated by a cancer-specific peptide:HLA complex can recognize the cancer-specific peptide in the context of the tumor, and kill the tumor cells.
Applicant also argues that the neo-antigenic epitopes bind to an HLA of the subject with a predicted binding affinity that fall within ranking criteria (i)-(v), and then are ranked according to such criteria. Thus, each species within the genus of neo-antigenic pepitopes identified by the claimed method has the required properties to be presented on the surf ace of APCs in a peptide:HLA complex and be recognized by cytolytic T cells. Applicant argues that they have described a genus of neo-antigenic epitopes identified by the claimed method having structural characteristics (the distinguishing identifying characteristics of I-II) that correlate to their functional characteristic (immunogenicity and eliciting a tumor-specific immune response in the subject), therefore correlating structure and function. Applicant argues that the genus of
neo-antigenic epitopes processed and presented by APCs has clear structural properties (presence of a missense or neoORF mutation, binding to HLA with a binding affinity that fall within ranking criteria (i)-(v)) that correlate to their function (immunogenicity and triggering of tumor-specific immune response). Applicant argues that one of skill in the art would be able to recognize the genus of neoantigenic
epitopes identified according to the claimed method and processed and presented by
APCs that are administered to a patient to treat cancer.
Applicant’s argument has been considered but are not persuasive. As an initial note, the peptides from Examples 19 and 20 do not appear to be ranked, only identified with their respective ID50. There also does not appear to be any selection of peptides to make at least two of the 30 ranked neoantigenic peptides based on the priority rankings (i)-(v). As previously discussed, the ranking criteria appears to encompass almost any peptide with an IC50 < 500mM. Given that immunogenic peptides primarily have IC50 < 500mM, the peptides within the ranked criteria (i)-(v) would include almost all immunogenic peptides. Furthermore, the three immunogenic peptides ALMS1, C6orf89 and FNDC3B appear to have IC50 of < 150 nm and had similar IC50 as the wild type peptide. Thus, none of the three immunogenic peptides were in the two top ranked categories.
As discussed previously, a peptide is defined by its amino acid sequence or by sufficient characteristics that one of ordinary skill in the art would be able to identify the specific peptide. Peptides vary in their amino acid sequences and knowledge of the amino acid sequence of one peptide does not identify the amino acid sequence of a second peptide in the absence of sufficient structural identity or identifying characteristics. Using a specific NetMHCpan algorithm and selecting peptides having a IC50 < 500mM and possibly be immunogenic would not sufficiently identify the structure of a neoantigenic polypeptide. Furthermore, the specification disclose that only about 5% of predicted peptides generated from missense mutations yielded detectable T cell responses.
Furthermore, out of the 46 peptides listed in Tables 9 and 10, Applicant has demonstrated that three induced immune responses in vitro, ALMS1 (TPTVPSSSF), C6orf89 (MPIEPGDIGC) and FNDC3B (WMSWAPPV). There does not appear to be any correlation between the structure of these peptides and the immunogenicity of these peptides. Furthermore, Applicant has not pointed to any difference in the amino acid structure of these immunogenic peptides and the structure of non-immunogenic peptides. One of skill in the art would not agree that Applicant was in possession of a method of administering the claimed genus of neo-antigenic epitopes because the specification does not disclose any species of ranked immunogenic neo-antigenic epitopes let alone a sufficient numbers of species with the genus of immunogenic neo-antigenic epitopes nor demonstrate any correlation between the structure and the function of the claimed neo-antigenic polypeptides. The Specification only disclose general methods for identifying and ranking the immunogenic neo-antigenic epitopes. But as stated previously, possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.
In addition, the claims require that the peptides be ranked according to the criteria (i)-(v), not just that the neo-antigenic peptides are within the criteria (i)-(v).
B.
Applicant argues that the instant disclosure is sufficient in light of the subject-specific and unique nature of the neo-antigenic epitopes processed and presented by APCs. Applicant argues that as stated above, the claims are directed to administering antigen presenting cells comprising one or more polypeptides comprising at least two of five top ranked neo-antigenic epitopes as identified and ranked by the claims, or T cells stimulated with the APCs, not administering the epitopes themselves. Applicant argues that the antigenic epitopes of the claimed invention are unique to the subject and the subject's tumor
Applicant argues that the claims are not to specific mutations, but to a
method of identifying mutations and producing cancer-specific CTLs using peptides containing such mutations. Applicant argues that '[T]he certainty required of [a patent] disclosure is not greater than that which is reasonable, having due regard to the subject matter involved.
Applicant further argues that the claims are not to specific mutations, but to a method of identifying mutations and producing cancer-specific CTLs using peptides containing such mutations. Applicant argues that because cancer-specific mutations may be unique to a particular patient, see it would not be reasonable to require disclosure of all possible cancer-specific mutations encompassed by the claims." Applicant argues that the instant disclosure provides a sufficient number of experimental demonstrations to support every element of the claimed method. To the extent the Office may expect that specific details to the level of sequence information of the polypeptides are required in order for the claim to meet the requirement of 35 U.S.C. § 112(a), written description, the Office is improperly requiring "every permutation within a generally operable invention be effective" to satisfy the written description standard.. Applicant argues that this is analogous to the issue of Vitiello.
Applicant argues that similar to the decision in Vitiello, it would be unreasonable and in fact impossible to require disclosure of all possible neo-antigenic polypeptides encompassed by the instant claims to satisfy the written description standard under 35 U.S.C. § l 12(a). Applicant further argues that even if such a standard existed, the application as-filed does not need to provide the amino acid sequence of every neo-antigenic polypeptide identified through the claimed method to show possession, because in this particular context, the actual amino acid sequence of the peptides (i.e., the specific order of the amino acids) is irrelevant. As described in (A)(2), the claimed structural characteristics of the peptides are correlated to their function of triggering a tumor-specific immune response.
Applicant’s arguments have been considered but are not persuasive. As previously discussed, methods of treating a subject diagnosed with having a neoplasia with a subject specific composition comprising administering the subject-specific composition comprising APCs comprising two or more ranked neoantigenic epitopes are practical applications of the identifying and ranking steps recited in the present claims. The specification does not appear to disclose any neo-antigenic peptides that have been ranked according to the criteria (i)-(v). It is noted that the neo-antigenic epitopes are critical to treat the subject. The APCs by themselves would not induce a cancer antigen-specific immune response.
Furthermore, administering a neo-antigenic peptide requires knowledge of the amino acid structure of the peptide. As discussed previously, it is not clear how the inventors had possession of the neo-antigenic epitopes that were ranked based on the criteria (i)-(v) when the specification does not disclose the ranking of any of the listed peptides identified by their amino acid structure. It is noted that the ranking limitation steps (i)-(v) were inserted into claim 1 to overcome the previous art rejections.
It has been interpreted that the neo-antigenic epitopes must be functional to treat the subject with a neoplasia which means they must be immunogenic. If the selected neo-antigenic peptides were not immunogenic, the administration of the neo-antigenic epitopes would not be a practical application of the identifying and ranking steps and the claims would not be directed to patentable subject matter.
The specification only discloses three peptides, ALMS1, C6orf89 and FNDC3B, capable of inducing an immune response. The Specification does not disclose the ranking of any of these immunogenic neo-antigenic epitopes. This is unlike what was found in Vitiello in which the Court stated that specification disclosed numerous peptides (approximately 320 peptides in Figures 4 and 5) that were capable of functioning to produce cancer-specific CTLs. Thus, the present application can be differentiated from in Vitiello in that the Specification does not appear to disclose any functional neo-antigenic peptides that have been ranked according to the criteria (i)-(v).
The specification does not include any ranked neo-antigenic epitopes in an order of decreasing priority as recited in the claims. The specification lists peptides along with their predicted and experimental IC50 using the NetMHCpan (version 2.4) algorithm. Out of the 46 peptides listed in Tables 9 and 10, Applicant has demonstrated that three induced immune responses in vitro. This is consistent with Applicant’s statement that about 5% of the peptides in this working example "of predicted peptides generated from missense mutations yielded detectable T cell responses. There does not appear to be any correlation between the structure of these peptides and their ability to induce immune responses.
A peptide is defined by its amino acid sequence or by sufficient characteristics that one of ordinary skill in the art would be able to identify the specific peptide. Peptides vary in their amino acid sequences and knowledge of the amino acid sequence of one peptide does not identify the amino acid sequence of a second peptide in the absence of sufficient structural identity or identifying characteristics.
The Federal Circuit addressed the application of the written description requirement to DNA-related inventions in University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997). The court stated that “[a] written description of an invention involving a chemical genus, like a description of a chemical species, requires a precise definition, such as by structure, formula, [or] chemical name, of the claimed subject matter sufficient to distinguish it from other materials.” Id. At 1567, 43 USPQ2d at 1405. The court concluded that “naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.” Id. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, Inc. V. Gen-Probe Inc., 296 F.3d 1316, 63 USPQ2d 1609 (Fed. Cir. 2002).
Applicant has not sufficiently described the genus of ranked immunogenic neo-antigenic epitopes to show they had possession of the claimed genus. Since the disclosure fails to provide sufficient relevant identifying characteristics, and because the genus is highly variant, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus as broadly claimed.
In response to Applicant’s argument that the claims are not to specific mutations, but to a method of identifying mutations and producing cancer-specific CTLs using peptides containing such mutations, the claims are drawn to a method of treating a subject diagnosed as having a neoplasia with a subject-specific composition, not a method of identifying mutations and producing cancer-specific CTLs as was claimed in Vitiello. The claims in Vitiello were not drawn to methods for treating cancer patients with the cancer cell-specific cytotoxic T lymphocytes.
In response to Applicant’s argument that the specific order of the amino acids is irrelevant, it is not clear how one of skill in the art would be capable of administering a polypeptide comprising at least 2 neo-antigenic epitopes without knowing the specific order of the amino acids in the neo-antigenic polypeptide to be administered. It would be impossible to administer a polypeptide comprising at least 2 neo-antigenic epitopes without knowing the amino acid sequence of the neo-antigenic epitopes. One of ordinary skill in the art would not be able to identify the amino acid structure of a neo-antigenic peptide by only knowing that the peptide had a missense or neoORF mutation and had an ID50 < 500mM to an MHC molecule.
In response to Applicant’s argument that the claimed structural characteristics of the peptides (i.e., distinguishing identifying characteristics) are correlated to their function of triggering a tumor-specific immune response, the specification does not disclose any criteria which correlate the structural characteristics of the immunogenic neo-antigens to their function. Given that Applicant states that only about 5% of the peptides of predicted peptides generated from missense mutations yielded detectable T cell responses, it is not clear how one of skill in the art could identify immunogenic neo-antigenic peptides based solely on general structural characteristics of the neo-antigenic peptides.
In response to Applicant’s argument that the Office is improperly requiring "every permutation within a generally operable invention be effective" to satisfy the written description standard, as previously discussed, the specification does not appear to disclose even one species of at least two neo-antigenic peptides that have been ranked according the criteria (i)-(v) as recited in the claims. As previously stated, Applicant inserted the ranking limitation steps (i) – (v) to obviate previous art rejections.
As discussed previously this is unlike what was found in Vitiello in which the Court stated that specification disclosed numerous peptides (approximately 320 peptides in Figures 4 and 5) that were capable of functioning to produce cancer-specific CTLs. Thus, the present application can be differentiated from in Vitiello in that the Specification does not disclose any functional neo-antigenic peptides that have been ranked according to the criteria (i)-(v) compared to approximately 320 function cancer-specific peptides disclosed in Vitiello. Furthermore, the claims in Vitiello were drawn to methods for producing cancer-specific cytotoxic T lymphocytes not to methods for treating cancer patients with the cancer cell-specific cytotoxic T lymphocytes.
Applicant further relies on UroPep63 to further support their position that they do not need to provide the amino acid sequence of every cancer-specific peptide identified through the claimed method to meet the written description requirement. Applicant states that in UroPep, Lilly contended that Ariad required the disclosure of a structural feature common to all members of the genus. Judge Bryson, sitting in designation, disagreed and the Federal Circuit affirmed. Judge Bryson found that either a common
chemical structure or a common physical structure (e.g., all compounds resembled an envelope in 3D) was sufficient to meet the structure function correlation for written description.
Applicant argues that in the present case, each species within the genus of cancer-specific peptides identified by the claimed method has several structural characteristics (i.e., distinguishing identifying characteristics (a)(i)-(a)(iv)), which give rise to a common physical structure, that is correlated to function (i.e.,immunogenicity and triggering an immune response). Applicant argues that as described in the Specification, validated HLA-peptide-binding prediction algorithms to predict the binding affinity of peptides with a known amino acid sequence to particular HLA Class I molecules were publicly available and well established at the priority date and described in the Specification.
Applicant argues that as in UroPep, because the genus of neo-antigenic polypeptides have a common physical structure that is correlated to the
function, one in the art would understand that Applicant was in possession of a method of treating cancer. Applicant argues that this is supported by Examples 19 and 20 that demonstrate that a ranked neoantigenic polypeptide identified by following step (a) of claim 1 or claim 19 generated a T cell response
Applicant’s argument has been considered but is not persuasive. The Court in UroPep found that in addition to the compounds expressly disclosed in the '124 patent, the jury heard undisputed evidence that hundreds of PDE5 inhibitors were known by July 1997 [276 F.Supp.3d 647]. Dr. Bell testified about the advanced state of the art regarding selective PDE5 inhibitors in July 1997: "There were hundreds of known inhibitors, selective inhibitors of PDE5 known at that time [Id]. This was a pretty mature area (explaining that hundreds of selective PDE5 inhibitors were known by July 1997); (explaining that skilled artisans were aware of hundreds of other selective PDE5 inhibitors beyond those expressly named in a 1995 review article) Id. The decision in UroPep disclosed that Lilly's expert Dr. Rotella admitted that tadalafil, as well as 118 other compounds in one sample paper published in 1995, were known PDE5 inhibitors before July 1997. Dkt. No. 343, Trial Tr. at 792-93. There was also evidence that at least two selective PDE5 inhibitors — in particular, sildenafil and zaprinast — had been subjected to human clinical testing long before July 1997, albeit for conditions other than BPH. Dkt. No. 344, Trial Tr. at 1293-94; see also Dkt. No. 342, Trial Tr. at 315-18. The Court found that given the evidence of the knowledge of a person of skill in July 1997 regarding PDE5 inhibitors, including tadalafil, a reasonable jury could have found that the Specification disclosed a sufficient number of representative species of selective PDE5 inhibitors Id.
The Court also disclosed that UroPep's expert Dr. Bell gave a lengthy description of the core chemical structure found in a number of selective PDE5 inhibitors, including tadalafil and compound E4021 (compound (d) in the '124 patent), as well as a number of other prior art compounds. [276 F.Supp.3d 653]. The Court also disclosed that the patent's disclosure of E4021 is therefore the disclosure of a species with a chemical structure shared by tadalafil (Id).
Thus, in UroPep the Court found that numerous PDE5 inhibitors were already known as well as a common core structure. This is not similar to the present application in which the Specification only demonstrated that three neo-antigenic polypeptides induced immune responses in vitro. This is consistent with Applicant’s statement that about 5% of the peptides in this working example "of predicted peptides generated from missense mutations yielded detectable T cell responses.
It is not clear what structural feature are common to all members of the genus of functional neo-antigenic epitopes. As previously discussed, a peptide is defined by its amino acid sequence or by sufficient characteristics that one of ordinary skill in the art would be able to identify the specific peptide. Peptides vary in their amino acid sequences and knowledge of the amino acid sequence of one peptide does not identify the amino acid sequence of a second peptide in the absence of sufficient structural identity or identifying characteristics. It is not clear where in the present claims the characteristics which give rise to a common physical structure, that is correlated to function (i.e.,immunogenicity and triggering an immune response) can be found . It is noted that the specification does not appear to include any ranking of immunogenic neo-antigenic epitopes based on the criteria (i)-(v). Thus, it is unclear how the genus of neo-antigenic epitopes have a common physical structure that is correlated to the function, given that there was no examples of neo-antigenic peptides ranked according to the characteristics (i)-(v).
C.
Applicant argues that the cases cited by the Examiner do not apply to the pending claims. Applicant argues that because the claims are not directed to devices or compositions of matter, but rather to methods of treating a subject diagnosed as having a neoplasia by administering APCs comprising neo-antigenic epitopes identified and ranked that fall within the criteria recited in the claims, the Office's reliance on Eli Lilly, Enzo Abbvie v. Janssen to support their written description position is misplaced.
Applicant argues that unlike Eli Lilly where cDNAs were claimed, Applicant
claims methods of making and producing a subject-specific composition comprising neo-antigenic polypeptides containing a neoORF or missense mutation of a subject and administering such a composition, as recited in claims 1 and 19. Further and in contrast to Eli Lilly, the claimed methods contain well-defined and reproducible steps such that one skilled in the art could readily identify neo-antigenic polypeptides made by the recited criteria of the claimed methods.
In addition, Applicant argues that unlike Enzo where the probes were claimed,
Applicant claims methods of making and producing a subject-specific composition comprising neoantigenic polypeptides that fall within specific criteria, as recited in claim 1, as well as administering such compositions, as recited in claim 19.
In response, as noted previously, the claims are drawn to methods of treating a subject comprising administering a subject-specific composition comprising APCs comprising at least two of five top ranked neo-antigenic epitopes that were ranked according to the criteria (i)-(v). As previously discussed, the specification does not disclose the ranking of any of the listed neo-antigenic peptides identified by their amino acid structure. Furthermore, as previously discussed, a peptide is defined by its amino acid sequence or by sufficient characteristics that one of ordinary skill in the art would be able to identify the specific amino acid sequence of the peptide. The specification only disclose general methods for identifying and ranking the neo-antigenic peptides. But as stated previously, possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.
Applicant further argues that in Abbvie v. Janssen, the claims at issue were directed to fully human antibodies that bind to IL-12. While the Specification of the Abbvie patents at issue disclosed over 300 structurally similar antibodies having
a range of IL-12 binding affinities, the Specification did not describe any common structural features or established correlation of classes of antibodies to encompass the entire genus, and relied on a trial and error approach to modify the individual amino acids to improve IL-12 binding affinity. Applicant argues that unlike Abbvie v. Janssen
where the antibodies were claimed, Applicant claims methods of making and producing a subject-specific composition comprising neo-antigenic polypeptides, as recited in claim 1, as well as methods of administering such a composition. Applicant argues that in contrast to the trial and error approach in Abbvie v. Janssen, the claimed methods contain well-defined and reproducible steps such that one skilled in the art could readily envision the genus of neo-antigenic polypeptides identified and produced by the recited methods. Applicant argues that one skilled in the art would be able to practice identifying and ranking the neo-antigenic polypeptides that fall within criteria (i)-(v) in future settings.
In response, as discussed above, it has been interpreted that methods for treating a subject comprising administering APCs comprising at least two the neo-antigenic peptides that were ranked according to criteria (i)-(v) would require knowledge of the amino acid structure of the immunogenic neo-antigenic peptides, which were identified using an algorithm based on whole genome or whole exome sequencing of the subject’s tumor cell. In addition, as discussed above, epitopes vary in their amino acid sequences and knowledge of the amino acid sequence of one epitope does not identify the amino acid sequence of a second epitope in the absence of sufficient structural identity or identifying characteristics.
It is noted that making monoclonal antibodies to an antigen is well established in the art. And just like with antibodies where knowing the amino acid sequence of one antibody does not tell you anything about the structure of a second antibodies, knowing the amino acid sequence of one functional epitope does not tell you anything about the amino acid sequence of a second functional epitope. And just like with antibodies in which one skilled in the art could not readily envision the genus of antibodies to a specific antigen using well established methods, one of skill in the art would not be able to readily envision the genus of neo-antigenic polypeptides that fall within criteria (i)-(v). As discussed previously, it is noted that the Specification does not include any ranking of neo-antigenic neoantigenic polypeptides according to the criteria (i)-(v). Thus, unlike Abbvie v. Janssen in which several species of antibodies were defined in the Specification, the Specification does not disclose any immunogenic neo-antigenic peptides that were ranked according to the criteria (i)-(v). It is further noted that the ranking limitation steps (i) – (v) were critical for obviating the previous art rejections.
The specification only disclose general methods for identifying the neo-antigenic peptides and then ranking the peptides, but does not disclose any immunogenic neo-antigenic peptides that were identified and ranked according to the criteria (i)-(v). As stated previously, possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.
In response, to Applicant’s arguments that the claims in Eli Lilly, Enzo, and Abbvie v. Janssen all were directed to compositions of matter, while the instant claims are directed to methods of producing a subject-specific composition comprising neo-antigenic polypeptides as well as methods of administering such a composition and that no trial and error is necessary to practice the invention as described and claimed, it is not clear how one can administer neo-antigenic peptides without knowing the specific amino acid structure of the immunogenic neo-antigenic peptides. The claims are not drawn to methods for identifying prospective immunogenic neo-antigens. Given that approximately 5% of predicted peptides generated from missense mutations yielded detectable T cell responses, it is not clear how two neo-antigenic peptides would be sufficient to adequately induce T cell responses.
In response to Applicant’s argument that they have fully described the steps to make these neo-antigenic polypeptides in individual patients and provided a sufficient number of examples of neo-antigenic polypeptides, the specification does not appear to disclose any neo-antigenic peptides that were ranked according to the criteria (i)-(v) that were immunogenic. As discussed previously, possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.
In addition, Applicant states that in Alonso, the claims were directed to therapeutic methods using human monoclonal antibodies. Applicant argues that while the Specification in Alonso disclose a single antibody, the specification neither characterized the antigens to which the genus of antibodies must bind, nor taught the structure, epitope characterization, binding affinity, specificity, or pharmacological properties common to the genus of antibodies implicated by the method. Applicant states that the Court found that the single antibody described in the Specification to be insufficiently representative to provide adequate written description for the genus of antibodies claimed implicated by the method. Applicant argues that unlike Alonso, here there is ample disclosure of actual neo-antigenic peptides successfully obtained by the recited process.
In response, as discussed previously, the specification does not disclose any immunogenic neo-antigenic peptide that were ranked according to the criteria (i)-(v) as set forth in the claims. The specification only disclose methods for obtaining possession of the neo-antigenic peptides, which is not sufficient to describe the peptides. A peptide is defined by its amino acid sequence or by sufficient characteristics that one of ordinary skill in the art would be able to identify the specific peptide. Peptides vary in their amino acid sequences and knowledge of the amino acid sequence of one peptide does not identify the amino acid sequence of a second peptide in the absence of sufficient structural identity or identifying characteristics.
The court in In re Alonso (Fed. Cir. 2008) citing In re Enzo, Enzo, 323 F.3d at 969 stated that
[F]or purposes of satisfying the written description requirement, it is not enough merely to disclose a method of making and identifying compounds capable of being used to practice the claimed invention.
The Specification only disclose how to identify neo-antigenic peptides ranked according to criteria (i)-(v). The claims encompass neo-antigenic polypeptides that will be discovered in the future. As discussed previously, the specification does not include the ranking of any of the listed neo-antigenic peptides by the criteria (i)-(v). Thus, the specification not disclose any neo-antigenic peptides ranked by the criteria (i)-(v) and thus does not disclose any species within the genus of neo-antigenic peptides that were to be administered to a subject.
Applicant further argues that in Rochester, the patent at issue claimed a method of administering a compound to a human to achieve a therapeutic effect but failed to disclose any such compound, suggestion of how to make it or otherwise obtain
it other than by trial and error research, or proffer any evidence that the inventors knew of the compound at the time the application was filed. Applicant argues that unlike Rochester, the current claims are drawn to a method of making a subject-specific composition. Applicant argues that upon faithful reproduction of the method steps by a person of skill in the art, the composition will differ from one sample to another as long as the biological sample is from a different patient each time, as is the nature of personal medicine.
In response to Applicant’s argument that In Rochester, the patent at issue claimed a method of administering a compound to a human to achieve a therapeutic effect but failed to disclose any suggestion of how to make it or otherwise obtain it other than by trial and error research, or proffer any evidence that the inventors knew of the compound at the time the application was filed, claim 6 in Rochester recited
A method for selectively inhibiting PGHS-2 activity in a human host, comprising
administering a non-steroidal compound that selectively inhibits activity of the
PGHS-2 gene product in a human host in need of such treatment, wherein the
ability of the non-steroidal compound to selectively inhibit the activity of the PGHS-
2 gene product is determined by:
a) contacting a genetically engineered cell that expresses human PGHS-2,
and not human PGHS-1, with the compound for 30 minutes, and exposing
the cell to a pre-determined-amount of arachidonic acid;
b) contacting a genetically engineered cell that expresses human PGHS-1,
and not human PGHS-2, with the compound for 30 minutes, and exposing
the cell to a pre-determined amount of arachidonic acid;
c) measuring the conversion of arachidonic acid to its prostaglandin
metabolite; and
d) comparing the amount of the converted arachidonic acid converted by each cell exposed to the compound to the amount of the arachidonic acid
converted by control cells that were not exposed to the compound, so that
the compounds that inhibit PGHS-2 and not PGHS-1 activity are identified.
Thus, the method steps provide a clear step-by-step roadmap to identify the pharmaceutical compositions. In Rochester, there are no identified compounds but several small molecules that were later determined to be capable of inhibiting PGHS-2 and not PGHS-1 were known in the art.
Like Rochester, the present specification only provides a step-by-step roadmap to identify the immunogenic neo-antigenic peptides ranked according to the criteria (i)(v).
The specification does disclose three immunogenic peptides ALMS1, C6orf89 and FNDC3B but the Specification does not demonstrate that the peptides were ranked according to the priority rankings (i)-(v). The Specification does not include any ranking of neo-antigenic polypeptides according to the priority rankings (i)-(v), only a general outline of the ranking system in Figure 8.
Furthermore, the three immunogenic peptides ALMS1, C6orf89 and FNDC3B appear to have IC50 of < 150 nm and had similar IC50 as the wild type peptide. Thus, none of the three immunogenic peptides were in the two top ranked categories.
Like what was found in In Rochester, the Specification only disclose how to obtain possession of the genus of neoantigenic polypeptides that have been ranked in order of decreasing priority and producing and administering at least two of the top ranked neo-antigenic polypeptides prioritized based on criteria (i)-(v).
35 USC § 103(a) rejections maintained
The rejection of claims 49-51, 58, 60, 64-69, 72 and 75 under 35 U.S.C. 103 as being unpatentable over Hacohen et al (WO 2011/143656 published November 17,2011, IDS), in view of Garbe et al (PloS ONE 6:e26517, pages 1-8, 2011), Schwitalle et al (Gastroenterology 134:988-997, 2008), Khalili et al (Oncoimmunology, 2012, 1:1281-1289, IDS) and Sette et al. (Molecular Immunology 31: 813-822, 1994, IDS) are maintained.
Hacohen disclose identifying a plurality of sequences comprising missense and/or neoORF mutations in the neoplasia, wherein identifying comprises sequencing a genome, transcriptome, or proteome of the neoplasia (paragraphs 55Fig 2). Hacohen disclose vaccine compositions comprising APC comprising neoantigenic peptides or an expression construct encoding a neoantigenic peptide to be administered to cancer patients. (paragraphs 136-140, Figs 2-3).
Hacohen disclose that the neoantigenic peptides and polypeptides bind an HLA protein. In some aspect the neoantigenic peptides and polypeptides binds an HLA protein with greater affinity than a wildtype peptide (paragraph 90). The neoantigenic peptide or polypeptide has an IC50 of at least less than 5000 nM, at least less than 500 nM, at least less then 250 nM, at least less than 200 nM, at least less than 150 nM, at least less than 100 nM, at least less than 50 nM or less.
Hacohen disclose that a patient may be vaccinated in the early period following
hematopoietic stem cell transplantation (HSCT) ( e.g. as is done for CLL, CML and other leukemias (paragraph 30). Hacohen further disclose that anti-PD-1 or anti-PD-L1 antibodies may be administered along with the neoantigenic peptides.
Hacohen doesn’t specifically rank the neoantigenic in order of decreasing priority although Hacohen does indicate that neoantigens with IC50 of at least less than 150 nM are preferred as well as neoantigenic peptides that bind an HLA protein with greater affinity than a wildtype peptide.
Garbe disclose that peptides from frameshift mutation exhibited high immunogenicity (page 1, 2nd column; page 3, 1st column to page 5, 2nd column).
MSI leads to production of abnormal proteins predominantly constituting of frameshift mutants that represent neo-antigens to the immune system (page 6, 1st column). Graber disclose that MSI+ tumors often exhibit marked lymphocytic infiltration, especially at the tumor invasion front in the stromal compartment, with a predominance of activated CD8+ T cells (Id).
Schwitalle disclose immune responses to frameshift-induced neopeptides in cancer patients (page 993, 1st column to page 994, 1st column). Schwitalle disclose that the high immunogenicity of mismatch repair-deficient tumors has been likely caused by the generation of a large number of tumor-specific FSPs (page 992, 1st column).
Thus, both Garbe and Schwitalle disclose the greater immunogenicity of frameshift-induced neopeptides. This would be likely because the peptides generated would be completely different than the wild-type peptides from the same protein and would be much less susceptible to tolerance.
Sette teaches utilization of quantitative assays to measure the binding of antigenic peptides to MHC class I molecules and disclose that binding affinities of peptides to class I molecules of 50 nM or less were preferable (Abstract; page 5591, 1st paragraph to page 5592, 1st paragraph). Sette disclosed that immunogenicity of the peptides correlated with the binding affinity of the peptides with the MHC molecule (Id). Sette disclose that their data have important practical implications from the point of view of peptide-based CTL vaccine development, because they illustrate how quantitative binding assays can be used to rapidly select peptide epitopes that have a high likelihood of being immunogenic for CTL responses (Id).
Khalili disclose that knowledge of a patient’s HLA type and missense mutation profile provides the opportunity to develop personalized peptide vaccines and evidence supporting the efficacy of vaccination strategies based on mutant epitopes has already been generated. Models of peptide-HLA binding affinity can facilitate the identification of novel and “personal” targets for cancer vaccines (p. 1281). Khalili et al teach the binding affinity of a peptide for HLA proteins is associated with the immunogenicity of the peptide, computational prediction is a convenient and practical first step toward the identification of optimal vaccine targets for cancer therapy. The ongoing development of peptide-MHC binding algorithms has benefitted from progressively more empirical binding data, allowing for increased prediction accuracy (p. 1282). Khalili demonstrate identifying mutated peptides with increased binding affinity to HLA (<50nM) relative to the wild-type peptides (>500nM) (Figures 2 and 3). Khalili d identified a subset of mutated peptides with superior HLA-binding affinity for the development of personalized peptide vaccines (p. 1288).
One of ordinary skill in the art would have been motivated to combine Hacohen, Khalili, Sette, Garbe and Schwitalle because they all concern the administration of antigenic peptides to a patient with cancer. Furthermore, Hacohen, Khalili, Garbe and Schwitalle all concern the administration of neoantigenic peptides to a cancer patient.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to rank mutated peptides in terms of their relative affinities to HLA and as compared to the wild type peptide affinity, and to produce a personalized peptide vaccine based on whether the peptide was from a frameshift (neoORF) mutation or a missense mutations, whether the peptide had a kD of < 150 nM, whether the neoantigenic missense peptide had a lower kD than the wild type-type peptide.
The art disclose that peptides from frameshift mutations were highly immunogenic. The art discloses that peptides having an IC50 of less than 150 nM were more likely to induce immune responses. The art discloses that peptides having an IC50 of greater than 500 nM were less likely to induce immune responses The art discloses that neoantigenic peptides have an IC50 less than its corresponding wild type peptide were preferred.
Thus, neoantigens from frameshift mutations would be preferred over neoantigens from missence mutations. Neoantigenic peptides in which their corresponding wild type peptide had a lower binding affinity to the specific MHC would be preferred over neoantigenic peptides in which their corresponding wild type peptide didn’t have a lower binding affinity to the specific MHC. Neoantigenic peptides with a higher binding affinity would be preferred over neoantigenic peptides having a weaker binding affinity to a specific MHC molecule. It is well within the level of the ordinary skill artisan to categorize, rank and compare mutated and wild type peptide affinities to HLA utilizing the methods taught by the cited prior art.
Absent unexpected results, based on the art, it would have been obvious to rank neoantigenic peptides according to the following criteria,
(i) a neoORF epitope that binds to an HLA of the subject with a Kd of < 500 nM
encoded by a sequence comprising a neoORF mutation,
(ii) an epitope that binds to an HLA of the subject with a Kd of < 150 nM encoded by
a sequence comprising a missense mutation, wherein the native cognate epitope has a
Kd of > 1000 nM,
(iii) an epitope that binds to an HLA of the subject with a Kd of <150 nM encoded
by a sequence comprising a missense mutation, wherein the native cognate epitope
has a Kd of <150 nM,
(iv) a neoORF epitope that binds to an HLA of the subject with a Kd of < 500 nM encoded by a sequence comprising a neoORF mutation,
(v) an epitope that binds to an HLA of the subject with a Kd of from greater than 150
nM to 500 nM encoded by a sequence comprising a missense mutation, wherein the
native cognate epitope has a Kd of from greater than 150 nM to 500 nM;
The rejections of claims 49-51, 58, 60, 64-69, 71, 72 and 75 under 35 U.S.C. 103 as being unpatentable over Hacohen et al (WO 2011/143656 published November 17,2011, IDS), in view of Garbe et al (PloS ONE 6:e26517, pages 1-8, 2011), Schwitalle et al (Gastroenterology 134:988-997, 2008), Khalili et al (Oncoimmunology, 2012, 1:1281-1289, IDS) and Sette et al. (Molecular Immunology 31: 813-822, 1994, IDS) in further view of Brix et al (US 2011/0318380, published December 29, 2011) are maintained.
Neither Hacohen, Khalili, Sette, Garbe nor Schwitalle disclose that the neoplasia is surgically treated and the composition is administered at the time of the surgery.
Brix disclose a combination therapy may involve
administration to an individual an antigen presenting cell presenting one or more of the antigenic peptides and surgery (paragraph 126).
One of ordinary skill in the art would have been motivated to apply Brix’s administration of an antigen presenting cell presenting one or more of the antigenic peptides along with surgery to Hacohen, Khalili, Sette, Garbe and Schwitalle’s method of treating a subject diagnosed as having a neoplasia with a subject-specific neoplasia vaccine composition comprising antigen present cells comprising ranked neoantigenic peptides because Hacohen, Khalili, Sette, Garbe, Schwitalle and Brix all involve the administration of antigenic peptides to cancer patients.
It would have been prima facie obvious to combine Hacohen, Khalili, Sette, Garbe and Schwitalle’s method of treating a subject diagnosed as having a neoplasia with a subject-specific neoplasia vaccine composition comprising antigen present cells comprising ranked neoantigenic peptides with Brix’s administration of an antigen presenting cell presenting one or more of the antigenic peptides along with surgery to have a method of treating a subject diagnosed as having a neoplasia with a subject-specific neoplasia vaccine composition comprising antigen present cells comprising ranked neoantigenic peptides at the time of surgery.
Applicant argues that the claimed method provides for the first time, the identification of a specific, improved subset of neo-antigenic epitopes (encoded by sequences comprising both neoORF and missense mutations) for use as a subject-specific composition comprising APCs comprising the neo-antigenic epitopes, or T cell simulated by the APCs, for treatment of the subject's neoplasia. Applicant argues that the Examples of the present application disclose the prioritization of immunizing peptides. Applicant argues that there is no teaching or suggestion in the cited references to select a subset of at least two of five top ranked neo-antigenic epitopes encoded by missense mutations and/or neoORF mutations. Applicant argues that none of the cited references disclose or suggest incorporating this improved subset of neo-antigenic epitopes containing missense mutations and/or neoORF mutations based on
ranked neo-antigenic mutations into APCs. In particular, Applicant further highlights two aspects of the claims, in the following sections (a) and (b), which are not disclosed or suggested by the cited references.
Applicant’s arguments have been considered but are not persuasive. Determining which particular peptides are the most likely to be immunogenic is well known in the art. Binding of a neo-antigenic peptide to a specific MHC molecule would be independent as to whether the peptide was from a missense mutation or with a neoORF mutation. The anchor residues of the peptides would help to determine their affinity to the MHC molecule. However, given that a peptide from a missense mutation would more closely resemble a related wild-type peptide than a peptide from a neoORF mutation, the peptide from a neoORF would more likely be immunogenic compared to a peptide from a missense mutation. As discussed above, Garbe disclose that peptides from frameshift mutation exhibited high immunogenicity (page 1, 2nd column; page 3, 1st column to page 5, 2nd column). Applicant acknowledges this by stating that “epitopes encoded by the sequences comprising neoORF mutations that are predicted to bind (Kd < 500 nM) are given the highest priority in the ranking criteria based on the absence of tolerance for these entirely novel sequences”.
In addition, it was well-known that the binding affinity of a peptide to an MHC molecule was correlated with the ability of a peptide to generate an immune response. Sette teaches utilization of quantitative assays to measure the binding of antigenic peptides to MHC class I molecules and disclose that binding affinities of peptides to class I molecules of 50 nM or less were preferable. Sette disclosed that immunogenicity of the peptides correlated with the binding affinity of the peptides with the MHC molecule (Id). Sette disclose that their data have important practical implications from the point of view of peptide-based CTL vaccine development, because they illustrate how quantitative binding assays can be used to rapidly select peptide epitopes that have a high likelihood of being immunogenic for CTL responses (Id). Sette disclose. an affinity threshold of approximately 500 nM. The art discloses that peptides having an IC50 of less than 150 nM were more likely to induce immune responses. The art discloses that peptides having an IC50 of greater than 500 nM were less likely to induce immune responses Thus, the importance of the affinity of a peptide to a particular MHC and the type of mutation, missense mutation vs neoORF mutation, in predicting the immunogenicity of the peptide was well known in the art. Absent unexpected results, it would have been obvious to one of skill in the art to have come up with the ranking system of Figure 8. It is noted that the specification does not appear to demonstrate any ranking of neoantigenic peptides.
In response, to Applicant’s argument that there is no teaching or suggestion in the cited references to select a subset of at least two of five top ranked neo-antigenic epitopes encoded by missense mutations and/or neoORF mutations, Hacohen discloses the selection of from one to 120 peptides (paragraph 87). Absent unexpected results it would have been obvious to select a subset of at least two of five top ranked neo-antigenic epitopes encoded by missense mutations and/or neoORF mutations.
Furthermore, as discussed previously, none of the listed peptides in the specification were ranked according to the criteria (i)-(v). Thus, the specification do not disclose any neo-antigenic peptides that have been ranked according to the criteria (i)-(v) and was shown to be antigenic. The specification only discloses the structure of three peptides, ALMS1, C6orf89 and FNDC3B, capable of inducing an immune response. The three immunogenic peptides ALMS1, C6orf89 and FNDC3B appear to have IC50 of < 150 nm and had similar IC50 as the wild type peptide. Thus, none of the three immunogenic peptides were in the two top ranked categories.
In addition, as discussed previously, the specification disclose that approximately 5% of predicted peptides generated from missense mutations yielded detectable T cell responses. Thus, more than two peptides would be required to dependably generate immune responses.
1.
Applicant argues that the identification of such an improved subset of neo-antigenic epitopes, as required by the amended claims, was not taught nor suggested by the cited references. Applicant argues that the ranking criteria set forth in claim 49 consider that epitopes encoded by sequences comprising neoORF mutations represent the highest priority form of neo-antigenic epitopes compared to the other four forms of neo-antigenic peptides recited in the instant claims. As set out in Example 6, information from 220 melanomas from different patients revealed that on average there were approximately 450 missense and 5 neoORFs per patient, however for a quarter of the patients, neoORF peptides could constitute nearly half to all of the 20 peptides predicted to be appropriate for vaccination. As noted in the specification, neoORFs represent excellent candidate neoepitopes because they are likely to be more specific (for lack of a wild type counterpart) and immunogenic (as a result of bypassing thymic tolerance). Applicant argues that for at least this reason, epitopes encoded by the sequences comprising neoORF mutations that are predicted to bind (Kd < 500 nM) are given the highest priority in the ranking criteria "based on the absence of tolerance for these entirely novel sequences and their exquisite tumor specificity’." Applicant argues that epitopes encoded by the sequences comprising missense mutations represent the second highest priority form of neo-antigenic peptides compared to the other four forms of neo-antigenic peptides recited in the instant claims. As noted in the specification, 91 samples of CLL were analysed and mis sense mutations were found to represent the most abundant class of mutation (90% of somatic mutations) - this observation is consistent with data from other cancer types that suggest that missense mutations are approximately 10-fold more abundant than neoORFs. Applicant argues that in view of this, one embodiment of the claimed methods focused on the analysis of epitopes generated by missense mutations.
Applicant argues that analysis of the binding characteristics of the neo-antigen data from the literature as well as candidate neoepitopes from the data in CLL revealed conceptual insights into the types of point mutations most likely to effectively create a T-cell response. In experiments to validate the HLA-binding of predicted mutated peptides, experimental binding was confirmed in 76.5% of peptides predicted with IC50 of< 150nM and 36% of peptides predicted with IC50 of 150-500nM.75. Applicant argues that as noted in the specification, a consistent feature of immunogenic neoepitopes was a predicted binding affinity < 500 nM (3 of 3 of immunogenic CLL peptides and 30 of 33 [91% ] of the historical functional neoepitopes) and the majority of these (92%) displayed predicted affinities < 150 nM. Unexpectedly, in most cases (3 of 3 immunogenic CLL peptides and 27 of 33 [82%] historical functional epitopes), the corresponding wildtype epitopes were also predicted to bind with comparable strong/intermediate(< 150 nM) or weak (150 - 500 nM) affinity. Applicant argues that in view of this, the teachings of the specification support the idea that two types of mutations are commonly observed among naturally occurring T-cell responses to neo-antigens; (1) mutations at positions that lead to substantially better binding to the MHC allele, presumably due to improved interaction with MHC, or (2) mutations at positions that do not significantly interact with MHC but instead presumably alter the T cell receptor binding. The distinction between these two types of mutations fits with the concept that the peptide can be considered as a "key', which must fit both the MHC and the TCR "locks" in order to stimulate cytolysis, allowing mutations to independently vary
MHC or TCR binding. Applicant argues that the class of epitopes encoded by sequences comprising missense mutations in which the native peptide is not predicted to bind (Kd > 1000 nM) and the mutated epitope is predicted to bind with trong/moderate affinity (Kd < 150 nM) is given the second highest priority in the ranking criteria. This class of peptides represents approximately 20% of naturally observed T-cell responses. Applicant argues that the class of peptides encoded by sequences comprising missense mutations predicted to encode a polypeptide that binds with a Kd of < 150 nM, wherein the native cognate protein has a Kd of < 150 nM, is given the third highest priority in the ranking criteria. This class of peptides is responsible for approximately almost 2/3 of naturally observed T cell responses.
Applicant argues that all the remaining peptides encoded by sequences comprising neoORF mutations are given the fourth highest priority. Despite not being predicted to bind, these are included based on the known false negative rate, potential binding to HLA-C, potential for presence of Class II epitopes and the high value of utilizing totally foreign antigens. The fifth highest priority is given to the subset of Group II with lower predicted binding affinities (150 - 500 nM). This class is responsible for approximately 10% of the naturally observed T-cell responses.
Applicant argues that it would not have been obvious to rank, as specifically claimed, neo-antigenic epitopes with a weak Kd value (i.e., higher number) higher than neo-antigenic epitopes with a strong Kd value (i.e., lower number).
Applicant’s arguments have been considered but are not persuasive. As previously discussed, Hacohen disclose identifying a plurality of sequences comprising missense and/or neoORF mutations in the neoplasia and administering the identified ne0-antigenic peptide. Hacohen disclose that the neoantigenic peptide has an IC50 of at at least less than 500 nM, at least less then 250 nM, at least less than 200 nM, at least less than 150 nM, at least less than 100 nM, at least less than 50 nM or less. Hacohen disclose that neoantigens with IC50 of at least less than 150 nM are preferred as well as neoantigenic peptides that bind an HLA protein with greater affinity than a wildtype peptide. In addition, the art disclose that peptides from frameshift mutations were highly immunogenic. Thus, neo-antigenic peptides from neoORF mutations would be preferred to neo-antigenic peptides from missense mutations. Furthermore, Sette disclosed that immunogenicity of the peptides correlated with the binding affinity of the peptides with the MHC molecule. The art disclose that peptides having an IC50 of less than 150 nM were more likely to induce immune responses and that peptides discloses that peptides having an IC50 of greater than 500 nM were less likely to induce immune responses. Thus, all the parameters listed in the criteria (i)-(v) to predict the immunogenicity of peptides were known in the art. Thus, absent unexpected results with the exact details and order for the criteria (i)-(v) in determining the immunogenicity of peptides it would have been obvious to predict the immunogenicity of peptides based on the criteria (i)-(v).
In this regard, the peptides from Examples 19 and 20 do not appear to be ranked, only identified with their respective ID50. There also does not appear to be any selection of peptides to make at least two of the five ranked neoantigenic peptides based on the priority rankings (i)-(v). As previously discussed, the ranking criteria appears to encompass almost any peptide with an IC50 < 500mM. Given that immunogenic peptides primarily have IC50 < 500mM, the peptides within the ranked groups (i)-(v) would include almost all immunogenic peptides. Furthermore, the three immunogenic peptides ALMS1, C6orf89 and FNDC3B appear to have IC50 of < 150 nm and had similar IC50 as the native peptide. Thus, none of the three immunogenic peptides were in the two top ranked categories.
2.
Applicant argues that post-filing data demonstrates the immunogenicity of the neoantigenic epitopes of the amended claims. Applicant argues that recent clinical trials conducted after the priority date of the application, utilized the methods of the invention to identify and administer a plurality of ranked neo-antigenic epitopes to cancer patients that were shown to be capable of inducing a T cell response. Applicant argues that the results of these clinical trials are reported in Ott (2017) and Keskin (2019). Applicant argues that both Ott(2017) and Keskin (2019) identified a plurality of sequences comprising mis sense and/or neoORF mutations in the neoplasia by sequencing a genome, transcriptome, or proteome of the neoplasia in the subject and sequencing a genome, proteome, or transcriptome of non-neoplastic cells from the subject, as required by the pending claims. Applicant argues that in addition, both Ott (2017) and Keskin (2019) generates a multiepitope vaccine. The subject-specific composition in Ott (2017) was made by following the steps set forth in the amended claims. As described in Ott (2017), all 6 patients showed enhanced multiepitope immunogenicity based on the use of a large repertoire of mutated epitopes and revealed a profile of clinical success not seen with prior treatment efforts and all 6 patients were disease free at a median follow-up of 25 months (range 20-32). Applicant argues that as noted in the paragraph bridging pages 6-7 of Ott 2017, the study utilized the ranking criteria according to the claimed subject matter to select neo-antigenic peptides for inclusion in a personalized neoplasia vaccine. Page 6-7 of Ott (2107) states, "[e]pitopes were chosen for inclusion on the basis of a predefined set of criteria in the following rank order: (1) neoORFs which included predicted binding epitopes; (2) high predicted affinity (<150nM) somatic single nucleotide variations due to anc/or residue changes; (3) high-affinity (<150nM) somatic single nucleotide variations due to mutations in positions other than anchor residues; (4) neoORFs with no predicted binding epitopes; (5) lower affinity ( <150-500nM) versions of (2) and (3)."
In addition, Applicant states that Keskin (2019) described a second study to treat glioblastoma (GBM). The subject-specific composition was made by following the steps set forth in the amended. Two patients were evaluated for an immune response (the remaining patients had received high doses of dexamethasone, a powerful immune suppressant) and both patients generated CD4+ and CD8+ responses. Applicant states that in this study in each of these two patients, a similar pattern of reactivity was observed in both the blood and among isolated post-treatment tumor-infiltrating ymphocytes, demonstrating that neoantigen T cells induced by the subject-specific composition were shown to traffic to intracranial tissue. Applicant argues that as noted in the paragraph on page 7 of Keskin (2019) under the heading "Identification of target epitopes for peptide design", the study utilized the ranking criteria according to the claimed subject matter to select neo-antigenic peptides for inclusion in a personalized neoplasia vaccine. Applicant states that page 7 of Keskin states, "[e]pitopes were chosen for inclusion based on a pre-defined set of criteria in the following rank order: (1) neoantigen open reading frames that included predicted binding epitopes; (2) sSNVs with high predicted affinity (<150 nM) due to changes in anchor residues; (3) sSNVs with high predicted affinity (<150 nM) due to mutations in positions other than anchor residues; (4) NeoORFs with no predicted binding epitopes; and (5) lower affinity (<150-500 nM) versions of (2) and (3)."
Applicant’s arguments have been considered but are not persuasive. Ott(17) discloses that epitopes were chosen for inclusion based on a pre-defined set of criteria in the following rank order:
NeoORFs which included predicted binding epitopes
High predicted affinity (< 150 nM) sSNVs due to anchor residue changes
High affinity (<150 nM) sSNVs due to mutations in positions other than anchor residues
NeoORFs with no predicted binding epitopes
Lower affinity (<150 – 500 nM) versions of (2) and (3)
Comparing the ranking system of Ott with that of the present claims there are notable differences.
NeoORFs which included predicted binding epitopes
(i) a neoORF epitope that binds to an HLA of the subject with a Kd of < 500 nM
encoded by a sequence comprising a neoORF mutation,
High predicted affinity (< 150 nM) sSNVs due to anchor residue changes
(ii) an epitope that binds to an HLA of the subject with a Kd of < 150 nM encoded by a sequence comprising a missense mutation, wherein the native cognate epitope has a Kd of > 1000 nM.
3. High affinity (<150 nM) sSNVs due to mutations in positions other than anchor residues
(iii) an epitope that binds to an HLA of the subject with a Kd of < 150 nM encoded by a sequence comprising a missense mutation, wherein the native cognate epitope has a Kd of < 150 nM,
NeoORFs with no predicted binding epitopes
(iv) a neoORF epitope that binds to an HLA of the subject with a Kd of > 500 nM encoded by a sequence comprising a neoORF mutation,
Lower affinity (<150 – 500 nM) versions of (2) and (3)
(v) an epitope that binds to an HLA of the subject with a Kd of from greater than 150 nM to 500 nM encoded by a sequence comprising a missense mutation, wherein the native cognate epitope has a Kd of from greater than 150 nM to 500 nM;
In comparing the ranking groups from Ott with the ranking groups (i)-(v) from the present claims it is apparent that the groups are distinct. There is no comparison in the affinity of neo-antigens to their MHC molecule with the affinity of wild type peptides to the MHC molecule. There is no differentiation in whether the mutation occurred in an anchor residue in the ranking system for the present claims. The affinity constants between the groups are different. There also does not appear to be any selection of neoantigenic peptides to administer at least two of the 5 top ranked neoantigenic peptides based on the priority rankings (i)-(v).
Furthermore, Ott discloses that 13–20 immunizing long peptides per patient with melanoma (with lengths of 15–30 amino acids) were synthesized and grouped into 4 separate immunizing pools. Ott discloses that a personalized neoantigen-targeting vaccine consisting of long peptides with lengths of 15–30 amino acids combined into 4 distinct immunizing peptide pools with 0.3mg of each peptide admixed with 0.5mg poly-ICLC per pool in a volume of 1ml was generated as described below, and was administered subcutaneously (SC) on days 1, 4, 8, 15, and 22 (priming phase) and weeks 12 and 20 (booster phase).
The present claims recite (c) administering a subject-specific composition that comprises (A) antigen-presenting cells (APCs) comprising one or more polypeptides comprising at least two of five top ranked neoantigenic epitopes encoded by the plurality of sequences comprising missense and/or neoORF mutations based on the ranking, or a polynucleotide encoding the at least two of five top ranked neo-antigenic epitopes one or more polypeptides or (B) T cells stimulated with the APCs of (A).
MPEP 716.02(d) states
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at “elevated temperatures” using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110C and 130C. The court affirmed the rejection of claims 1-7 and 9-10 because the term “elevated temperatures” encompassed temperatures as low as 60C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.).
The unexpected results demonstrated in Ott are not commensurate in scope with the present claims.
Furthermore, it appears that the ranking criteria disclosed in Keskin and the ranking criteria for Ott are identical and thus distinct from the ranking criteria as set forth in the present claims. In addition, the administration protocol of Keskin was similar to that shown in Ott, up to 20 long (15-30 amino acids) peptides were divided into pools of 3–5 peptides admixed with poly-ICLC were administered to patients with glioblastoma. The peptides were administered with five priming steps followed by one or one or 2 boosts (Figure 1). There also does not appear to be any selection of neoantigenic peptides to make at least two of the 5 top ranked neoantigenic peptides based on the priority rankings (i)-(v). As previously discussed, the ranking criteria appears to encompass almost any peptide with an IC50 < 500mM. Given that immunogenic peptides primarily have IC50 < 500mM, the peptides within the ranked groups (i)-(v) would include almost all immunogenic peptides. Furthermore, the three immunogenic peptides listed in the specification, ALMS1, C6orf89 and FNDC3B appear to have IC50 of < 150 nm and had similar IC50 as the wild type peptide. Thus, none of the three immunogenic peptides were in the two top ranked categories.
With respect to Keskin, given that the specification discloses that approximately 5% of predicted peptides generated from missense mutations yielded detectable T cell responses, mixtures of up to 20 long peptides along with an adjuvant such as poly-IC would be expected to induce an immune response to at least one of those peptides. It is not clear that the results were unexpected.
Summary
Claims 49-51, 58, 60, 64-69, 71, 72 and 75 stand rejected
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/MARK HALVORSON/ Primary Examiner, Art Unit 1646