DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination under 37 CFR 1.114 after Final Rejection
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant’s submission filed on 24 October 2025 has been entered.
Status of Claims
Claims 1-14 are pending.
Claims 1-14 are rejected.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. §119(e) or under 35 U.S.C. §120, §121, or §365(c) is acknowledged. Applicant has complied with all of the conditions for receiving the benefit of an earlier filing date under 35 U.S.C. §120 or §365(c). As previously discussed, claims 1-14 have the effective filing date of 31 January 2020.
Claim Rejections - 35 U.S.C. § 112
35 U.S.C. § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. §112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. §112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
35 U.S.C. §112(a) and pre-AIA 35 U.S.C. §112, first paragraph require that the specification include the following (MPEP 2161 (I)):
(A) A written description of the invention;
(B) The manner and process of making and using the invention (the enablement requirement); and
(C) The best mode contemplated by the inventor of carrying out his invention.
Claims 1-14 are rejected under 35 U.S.C. §112(a) or 35 U.S.C. §112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contain(s) subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1-14 fail to comply with the written description requirement because they do not adequately describe the manner and process of making and using the invention; and
Claims 1-14 fail to comply with the written description requirement, because the claim text(s) recite(s) limitations which are not described in the specification and/or which encompass a claim breadth which is not supported by the specification.
Claim 1 recites: "A method...comprising administering to a patient suffering from the disease or condition, a peptide that constitutively binds at least one of p38 MAPK and ERK MAPK."
Claim 8 recites: "A method...comprising administering to a patient suffering from the disease or condition, a peptide that interferes with at least one of the p38 MAPK-COX2-PGE2 and ERK MAPK-CX3CL1-xCX3CL1 pathways."
Claims 2 and 9 recite: "..., wherein the peptide is a synthetic peptide mimetic of at least a portion of a modified STEP protein."
Claims 3 and 10 recite: "..., wherein the synthetic peptide mimetic comprises at least a portion of the KIM domain of the modified STEP protein."
Claims 5 and 12 recite: "..., wherein the synthetic peptide mimetic comprises a portion of a KIS domain of the modified STEP protein."
However, it is noted that Applicant has not supplied any nucleic acid or amino acid sequence information so as to enable the practitioner to identify the portions of the STEP protein, KIM domain and KIS domain which are encompassed by the peptide, per claims 1 and 8. It is indicated in the claims that only '(at least) a portion' of each of these peptides is included in the synthetic peptide mimetic.
Although instant Figure 10 shows two synthetic peptides (STEP61 and TAT-STEP-myc peptide) which comprise KIM and KIS domains in which specific amino acid sites are labeled (i.e., S221, T231, and S244), it is not clear what the entire sequence of each of these domains is in order to give the substitution of these amino acids functional significance and credibility within the context of the entire domain(s). The specification recites: " Fig. 10 is a schematic illustration of the STEP61 protein (upper) and an exemplary STEP peptide mimetic (lower) according to an embodiment of the present disclosure...The threonine and serine residues in the kinase specificity sequence (KIS) were mutated to glutamic acid to render the peptide resistant to degradation" (originally-filed specification, pg. 10, para. [0105]); and "A point mutation was introduced by site-directed mutagenesis...at serine 221 within the KIM domain (S221A) to render the peptide constitutively active in terms of its ability to bind to its substrate" (spec., pg. 14, para. [0116]).
Although KIM and KIS domains are referred to as so-called consensus sequences, the relevant art-related literature shows that both domains do not encompass only one (amino acid) sequence. For example, Munoz et al. ((2003) Biochem. J. 372: 193-201 (previously cited and on the record)) teaches that several classes of interaction sites for MAPKs (mitogen-activated protein kinase) have been defined, which are present in a wide array of MAPK-interacting molecules (pg. 193, column 2, lines 1-8). The described study shows that molecular determinants outside the KIM exist that are important for the differential association of PTP-SL and STEP, with ERK1/2 and p38α, and suggest that the non-catalytic amino-acid regions C-terminal to the KIM on PTP-SL and STEP regulate their selective binding to these MAPKs. These regions have been termed here as kinase-specificity sequences (KISs) (pg. 195, column 2, last 5 lines thru pg. 196, column 1, lines 1-2). Figure 8 shows an alignment of the KIM and KIS sequences of, minimally, STEP (residues 42-107) (Munoz et al., pg. 199, Fig. 8).
Figure 8 in Munoz et al. shows three different amino acid sequences for the KIM and KIS domains. The one sequence which may be most closely related to the instantly-claimed subject matter (which describes a modified STEP protein) is the sequence identified as "STEP". However, the KIM and KIS domains are encompassed by a STEP sequence which lies between amino acid residues (42) and (107)- which does not encompass the labeled/numbered amino acids indicated on instant Figure 10 (i.e., 221, 231 and 244).
That is, without the amino acid sequence of the peptide described in the claimed subject matter, one of ordinary skill in the art would be unable to make and practice the invention, which is a method for the prevention, treatment, or amelioration of a medical disease or condition associated with inflammation caused by glutamate excitotoxicity comprising administering to a patient suffering from the disease or condition, a peptide. The practitioner would be unable to produce a synthetic peptide mimetic which has the characteristics of said peptide mimetic as described in claims 1, 6-8, 13 and 14.
To overcome this rejection, Applicant may attempt to demonstrate (by means of argument or evidence) that the original disclosure establishes that he or she was in possession of the claims, or the claim(s) may be amended to recite an amino acid sequence that is supported by the specification (although the latter option does not appear to be feasible in view of the lack of a submitted SEQ ID listing).
Claim Rejections - 35 U.S.C. § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. §102 and §103 (or as subject to pre-AIA 35 U.S.C. §102 and §103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. §102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-7 are rejected under 35 U.S.C. §102(a)(1)/(a)(2) as being anticipated by Paul (Pub. No. WO 2012/037397 A2).
Paul addresses the limitations of claims 1, 2, 3, 4, 5, 6 and 7.
Regarding claim 1, pertaining to a method for the prevention, treatment, or amelioration of a medical disease or condition associated with inflammation caused by glutamate excitotoxicity comprising administering to a patient suffering from the disease or condition, a peptide that constitutively binds at least one of p38 MAPK and ERK MAPK,
Paul teaches that brain injury resulting from ischemic insults such as stroke, post-traumatic lesions and a variety of neurological disorders frequently causes significant neuro-degeneration resulting in mild to severe impairment and even death to those suffering from these injuries. Various studies implicate excitotoxic glutamate receptor activation in neurodegeneration following ischemic insults, post-traumatic lesions and a range of other neurological disorders (pg. 1, para. [004]-[005]). In addition, glutamate-mediated NMDAR stimulation leads to the activation of multiple signaling pathways that are involved in the propagation and maintenance of the inflammatory response in the injured brain (pg. 4, para. [024]).
Paul shows that, according to some embodiments, the described disclosure provides for the prevention, treatment, or amelioration of brain injury caused by excessive glutamate release and oxidative stress, which is considered to read on "inflammation caused by glutamate excitotoxicity". Accordingly, the described disclosure also provides STEP-derived peptides which can be delivered to the brain of a patient who is or has suffered from an incident, such as a stroke, resulting in this type of injury (pg. 7, para. [037]). Because the STEP protein is known to interfere with NMDAR (N-methyl-D-aspartate receptor), which is involved in the inflammatory response, a constitutively active peptide based on the STEP protein is a likely candidate for treatment, amelioration and/or prevention of ischemic brain damage (pg. 6, para. [030]). To determine the efficacy of the peptide in attenuating ischemic brain injury, a TAT-STEP peptide was administered intravenously immediately before or 1.5 hr after the onset of stroke (pg. 14, para. [088]). Based on findings (that sustained NMDAR stimulation results in degradation of active STEP leading to secondary activation of p38 MAPK that triggers cell death pathways), a constitutively active form of a STEP peptide that can bind irreversibly to p38 MAPK was generated (pg. 8, para. [039]).
Regarding claim 2, based on findings (that sustained NMDAR stimulation results in degradation of active STEP leading to secondary activation of p38 MAPK that triggers cell death pathways), a constitutively active form of a STEP peptide that can bind irreversibly to p38 MAPK was generated (pg. 8, para. [039]).
Regarding claims 3 and 5, Figs. 1 and 2 are schematic diagrams of STEP61 and STEP46, respectively, indicating the positions of, minimally, the kinase interacting motif (KIM), and the kinase specificity sequence (KIS) (pg. 5, para. [028]; and Fig. 1).
Regarding claim 4, because the STEP protein is known to interfere with NMDAR (N-methyl-D-aspartate receptor), a constitutively active peptide based on the STEP protein is a likely candidate for treatment, amelioration and/or prevention of ischemic brain damage (pg. 6, para. [030]). Figs. 5 and 6 are schematic illustrations of the described constitutively active STEP-derived peptides. In Fig. 6, the phosphorylation sites in both the KIM and KIS domains have been altered (pg. 7, para. [037]).
Regarding claim 6, dephosphorylation of two sites in the KIS domain selectively results in ubiquitin-mediated proteasomal degradation of the active form of STEP. These findings imply that ubiquitin-mediated proteasomal degradation of active STEP may also lead to secondary activation of p38 MAPK (pg. 6, para. [031]). Therefore, it may be desirable to produce an active STEP-derived peptide that remains stable and is not susceptible to ubiquitin-mediated proteasomal degradation in vivo (pg. 6, para. [032]). Figure 4 is a schematic illustration of a STEP-derived peptide according to an embodiment of the described disclosure, wherein Ser49 has been converted to alanine, which is non-phosphorylatable and Thr 59 and Ser 72 are converted, to glutamic acid to mimic the phosphorylatable form (pg. 7, para. [033]; and Fig. 4).
Regarding claim 7, Figs. 5 and 6 are schematic illustrations of the described constitutively active STEP-derived peptides including a TAT sequence at the N-terminal of the peptide. TAT is an 11 amino acid peptide that renders peptide sequences cell permeable and enables these peptides to cross the blood brain barrier (pg. 7, para. [037]).
Claim Rejections - 35 U.S.C. § 103
The rejection of Claims 1-14 under 35 U.S.C. §103 as being unpatentable over Adam et al.in view of Deb et al., and Singer et al., in the Final Office Action mailed on 25 June 2025, is withdrawn in view of further search and consideration of the claimed subject matter.
The following is a quotation of 35 U.S.C. §103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. §102(b)(2)(C) for any potential 35 U.S.C. §102(a)(2) prior art against the later invention.
Claims 1-14 are rejected under 35 U.S.C. §103 as being unpatentable over Paul (Pub. No. WO 2012/037397 A2) in view of Singer et al. (Am. J. Physiol. Lung Cell. Mol. Physiol. 2003, 285: L1087-L1098).
[Singer et al. cited in the Final Office Action mailed 25 June 2025.]
Paul addresses the limitations of claims 1-7 in the 35 §USC 102(a)(1)/(a)(2) rejection above.
Paul addresses some of the limitations of claim 8.
Regarding claim 8, pertaining to a method for the prevention, treatment, or amelioration of a medical disease or condition associated with inflammation caused by glutamate excitotoxicity comprising administering to a patient suffering from the disease or condition, a peptide that interferes with p38 MAPK,
Paul teaches that brain injury resulting from ischemic insults such as stroke, post-traumatic lesions and a variety of neurological disorders frequently causes significant neuro-degeneration resulting in mild to severe impairment and even death to those suffering from these injuries. Various studies implicate excitotoxic glutamate receptor activation in neurodegeneration following ischemic insults, post-traumatic lesions and a range of other neurological disorders (pg. 1, para. [004]-[005]). In addition, glutamate-mediated NMDAR stimulation leads to the activation of multiple signaling pathways that are involved in the propagation and maintenance of the inflammatory response in the injured brain (pg. 4, para. [024]).
Paul shows that, according to some embodiments, the described disclosure provides for the prevention, treatment, or amelioration of brain injury caused by excessive glutamate release and oxidative stress, which is considered to read on "inflammation caused by glutamate excitotoxicity". Accordingly, the described disclosure also provides STEP-derived peptides which can be delivered to the brain of a patient who is or has suffered from an incident, such as a stroke, resulting in this type of injury (pg. 7, para. [037]). Because the STEP protein is known to interfere with NMDAR (N-methyl-D-aspartate receptor), a constitutively active peptide based on the STEP protein is a likely candidate for treatment, amelioration and/or prevention of ischemic brain damage (pg. 6, para. [030]). To determine the efficacy of the peptide in attenuating ischemic brain injury, a TAT-STEP peptide was administered intravenously immediately before or 1.5 hr after the onset of stroke (pg. 14, para. [088]). Based on findings (that sustained NMDAR stimulation results in degradation of active STEP leading to secondary activation of p38 MAPK that triggers cell death pathways), a constitutively active form of a STEP peptide that can bind irreversibly to p38 MAPK was generated (pg. 8, para. [039]).
Paul further teaches that the secondary but not the primary activation of the p38 MAPK pathway correlate with the expression of cyclooxygenase-2 (COX-2), a key enzyme that is linked to p38 MAPK activation and is involved in inflammatory response and reactive oxygen species generation (pg. 14, cont. para. [086]).
Paul does not show: 1) a peptide that interferes with at least one of the p38 MAPK-COX2-PGE2 and ERK MAPK-CX3CL1-xCX3CL1 pathways [Claim 8].
Singer et al. provides information from which one of ordinary skill in the art would have understood that the peptide p38 MAPK inhibitors, shown by Paul, would have also interfered with the p38 MAPK-COX2-PGE2 pathway, by way of addressing the limitations of claim 8.
Singer et al. shows a study in which the data indicates that p38 MAPK affects COX-2 expression via separate signaling pathways. p38 MAPK participates in the regulation of COX-2 mRNA stability (pg. L1087, column 1, Abstract). The presented data demonstrate that inhibition of p38 MAPK decreases the steady-state levels of cytokine-stimulated COX-2 expression (pg. L1096, column 2, para. 1 thru pg. L1097, column 1, lines 1-2). Secretion of PGE2 was also examined in response to changes in COX-2 expression as a measure of COX-2 activity (pg. L1090, column 2, last line thru pg. L1091, column 1, lines 1-2). p38 MAPK mediates the responses of IL-1β involved in the regulation of, minimally, COX-2 expression, and PGE2 synthesis (pg. L1097, column 2, para. 1).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have understood that the method for the prevention, treatment, or amelioration of a medical disease or condition associated with inflammation, comprising administering a peptide that constitutively binds at least one of p38 MAPK and ERK MAPK, as shown by Paul, would also have interfered with pathways driven by p38 MAPK expression, such as the p38 MAPK-COX2-PGE2 pathway [Claim 8], with a reasonable expectation of success, because Singer et al. shows that inhibition of p38 MAPK decreases the steady-state levels of cytokine-stimulated COX-2 expression, which, in turn, would decrease the level of PGE2, because COX-2 regulates the expression of PGE2 (MPEP 2143 (I)(G)).
Even in the absence of Singer et al., one of ordinary skill in the art would have understood that a peptide which constitutively binds to and interferes with p38 MAPK expression would have interfered with pathways driven by p38 MAPK expression, such as the p38 MAPK-COX2-PGE2 pathway [Claim 8], with a reasonable expectation of success (MPEP 2144 (I)). In addition, Paul teaches that the secondary activation of the p38 MAPK pathway correlates with the expression of cyclooxygenase-2 (COX-2), a key enzyme that is linked to p38 MAPK activation (pg. 14, cont. para. [086]).
One of ordinary skill in the art would have been motivated to have made that modification, because Singer et al. teaches that posttranscriptional modification of COX-2 gene expression is an important mechanism affecting the inflammatory response in airway smooth muscle (pg. L1088, column 1, para. 1). The presented data demonstrate that inhibition of p38 MAPK decreases the steady-state levels of cytokine-stimulated COX-2 expression (pg. L1096, column 2, para. 1 thru pg. L1097, column 1, lines 1-2). That is, determining that controlling the gene expression of COX-2 via p38 MAPK would provide a different therapeutic approach to treating airway inflammation (MPEP 2143 (I)(F,G)).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Paul further addresses the limitations of claims 9, 10, 11, 12, 13 and 14.
Regarding claim 9, based on findings (that sustained NMDAR stimulation results in degradation of active STEP leading to secondary activation of p38 MAPK that triggers cell death pathways), a constitutively active form of a STEP peptide that can bind irreversibly to p38 MAPK was generated (pg. 8, para. [039]).
Regarding claims 10 and 12, Figs. 1 and 2 are schematic diagrams of STEP61 and STEP46, respectively, indicating the positions of, minimally, the kinase interacting motif (KIM), and the kinase specificity sequence (KIS) (pg. 5, para. [028]; and Fig. 1).
Regarding claim 11, because the STEP protein is known to interfere with NMDAR (N-methyl-D-aspartate receptor), a constitutively active peptide based on the STEP protein is a likely candidate for treatment, amelioration and/or prevention of ischemic brain damage (pg. 6, para. [030]). Figs. 5 and 6 are schematic illustrations of the described constitutively active STEP-derived peptides. In Fig. 6, the phosphorylation sites in both the KIM and KIS domains have been altered (pg. 7, para. [037]).
Regarding claim 13, dephosphorylation of two sites in the KIS domain selectively results in ubiquitin-mediated proteasomal degradation of the active form of STEP. These findings imply that ubiquitin-mediated proteasomal degradation of active STEP may also lead to secondary activation of p38 MAPK (pg. 6, para. [031]). Therefore, it may be desirable to produce an active STEP-derived peptide that remains stable and is not susceptible to ubiquitin-mediated proteasomal degradation in vivo (pg. 6, para. [032]). Figure 4 is a schematic illustration of a STEP-derived peptide according to an embodiment of the described disclosure, wherein Ser49 has been converted to alanine, which is non-phosphorylatable and Thr 59 and Ser 72 are converted, to glutamic acid to mimic the phosphorylatable form (pg. 7, para. [033]; and Fig. 4).
Regarding claim 14, Figs. 5 and 6 are schematic illustrations of the described constitutively active STEP-derived peptides including a TAT sequence at the N-terminal of the peptide. TAT is an 11 amino acid peptide that renders peptide sequences cell permeable and enables these peptides to cross the blood brain barrier (pg. 7, para. [037]).
Response to Arguments
Applicant’s arguments, pp. 4-5, filed 24 October 2024, with respect to the prior art references cited in the 35 U.S.C. §103 rejection, have been fully considered but they are moot because the arguments do not apply to the references as they are applied in the context of the current rejection, or as new grounds following further search and consideration of the claimed subject matter.
1. Applicant remarks (pg. 4, para. 1-3) that the primary reference of Adam is non-analogous prior art, and is directed to dermatological disorders, specifically rosacea, and studies epidermal keratinocytes. The secondary reference of Deb focusses on neuroprotection during ischemic insult and does not demonstrate or suggest efficacy in treating inflammation per se, nor does it address the downstream inflammatory cascades.
However, in response to Applicant, neither Adam et al. nor Deb et al. are cited in this Office Action. The previously-cited rejection under 103 over Adam et al.in view of Deb et al., and Singer et al., in the Final Office Action mailed on 25 June 2025, was withdrawn in view of further search and consideration of the claimed subject matter. See under Claim Rejections 35 USC §103 above.
2. Applicant remarks (pg. 4, para. 4) that Singer discloses only small-molecule, SB203580, a non-peptidic hetero-aromatic compound, inhibition of p38 MAPK in lung airway myocytes. Singer contains no disclosure of peptide-based therapeutics, no STEP-derived sequences, and no binding of inhibitors to ERK MAPK or to the CX3CL1 axis. Singer et al. therefore does not remedy the deficiencies of Adam and Deb.
However, in response to Applicant, Singer et al. was cited to address one of the limitations of claim 8, with regard to the relationship between p38 MAPK and COX-2. Paul is cited above to address the limitations regarding the synthetic peptide mimetic and the method for using said mimetic with regard to claim 8 (and claim 1).
Conclusion
No claims are allowed.
This Office action is a Non-Final action. A shortened statutory period for reply to this action is set to expire THREE MONTHS from the mailing date of this action.
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/SMP/Examiner, Art Unit 1651
/Michelle F. Paguio Frising/Primary Examiner, Art Unit 1651