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 .
Priority
Priority to US 63/089,268, filed 10/8/2020, is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) were submitted on 8/2/2023, 12/10/2024, and 2/19/2025, before the mailing of a first office action. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
The information disclosure statement (IDS) submitted on 3/31/2026 was filed after the mailing date of the non-final office action on 11/21/2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of the Claims
Claims 1-7, 11, 16-20, 22-25, and 28 are pending. Claims 1-7, 11, 16-20, 22-25, and 28 are under examination. Claims 8 and 9 are canceled.
Claim Objections
Response to Arguments
Claims 2-9 were previously objected to. Applicant’s arguments, see Applicant’s Reply page 8, para. 2, filed 2/9/2026, with respect to claims 2-7 have been fully considered and are persuasive. The objection to claims 2-7 has been withdrawn.
Claims 8 and 9 have been canceled, making the objection to these claims moot.
Claim Rejections - 35 USC § 112
Claims 9, 17, and 18-20 were previously rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Response to Arguments
Regarding claim 9, this claim has been canceled, rendering this rejection moot.
Applicant’s arguments, see Applicant’s Reply page 8, para. 3, filed 2/9/2026, with respect to claims 17-20 have been fully considered and are persuasive. The rejection of claims 17-20 has been withdrawn.
Claim Rejections - 35 USC § 102
Claims 1, 9, 11, 16, and 17 were previously rejected under 35 U.S.C. 102(a)(1) as being anticipated by Thor et al. (US 10,086,034, filed 1/27/2016).
Response to Arguments
Applicant’s arguments, see Applicant’s Reply page 9, para. 2, filed 2/9/2026, with respect to claims 1, 9, 11, 16, and 17 have been fully considered and are persuasive. . Therefore, the rejection has been withdrawn. Claim 9 is canceled, rendering that rejection moot. However, upon further consideration, a new ground of rejection is made below.
Claim Rejections - 35 USC § 103
Response to Arguments
Applicant’s arguments, see Applicant’s Reply page 8, para. 3, filed 2/9/2026, with respect to claims, with respect to the rejection of claims 2-8, 18-20, and 24 under USC 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. Claim 8 is canceled, rendering that rejection moot. However, upon further consideration, a new ground of rejection is made below.
New Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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, 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-5, 11, 16, 17, 22, 23, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Thor et al. (US 10,086,034, filed 1/27/2016) in view of Rovero et al. (Rovero, et al. Neuropeptides 13.4: 263-270 (1989)) as evidenced by Deal et al. (Deal, et al. Journal of medicinal chemistry 35.22: 4195-4204 (1992)).
Regarding claim 1, claim 1 recites:
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Thor et al. discloses the following compound:
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(Thor et al., col. 11, line 39).
Thor does not disclose a compound where in Lys is missing.
However, Rovero discloses that removing the residue preceding Asp 4 has minimal effect upon the binding activity of NKA, the peptide from which GR64349 is derived:
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(Rovero, et al., page 266, Table 3).
In the above table, the R.P.A. experiment is the NK-2 system of interest (Rovero et al., page 265, col. 1, para. 1). Rovero demonstrates that the activity does not significantly change until the NKA peptide is reduced to residues 5-10, making residues 4-10 the critical residues. Residues 4-10 of NKA correspond to Asp4-Ser5-Phe6-Val7-Gly8-Leu9-Met10. (Deal et al., page 4195, Fig. 1).
Furthermore, Rovero discloses that the NKA (4-10) peptide has the most activity against the NK-2 system: “However, while the activities of these compounds in the NK-1 (D.C.A.) and NK-3 (R.P.V.) systems decrease in parallel with the shortening of the peptide chain, a different pattern is observed in the NK-2 system where the most active compound is NKA (4-lo), twice as potent as NKA. These findings point to the fundamental role of Asp4 in the activation of NK-2 receptors.” (Rovero et al., page 266, col.2, para. 4).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to truncate peptide GR64349 disclosed by Thor as suggested by Rovero to arrive at the claimed invention.
A person of ordinary skill in the art would have a reasonable expectation of success of truncating GR64349 as suggested by Rovero because of the data that shows that the truncated peptide should bind properly. A person of ordinary skill in the art would shorten the peptide to this specific length and sequence to gain the activity boost described above by Rovero, or change the pharmacokinetics of the peptide by altering polarity or size.
Consequently, claim 1 is obvious over Thor et al. in view of Rovero et al., as evidenced by Deal et al. and rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further limits Xaa3 to Ser and B to Met-NH2. In Thor, Xaa3 is Ser and B is Met-NH2.
Consequently, claim 2 is obvious over Thor et al. in view of Rovero et al., as evidenced by Deal et al. and rejected.
Regarding claim 3, claim 1 is obvious as described above. Claim 2 further recites the peptide compound of claim 1, wherein Xaa1 is absent, Xaa3 is Ser, and B is Nle-NH2, or a pharmaceutically acceptable salt thereof (Compound B; SEQ ID NO: 2).
The peptide GR64349 disclosed by Thor has Xaa1 as Lys, Xaa3 as Ser, and B is Met-NH2. However, Rovero discloses that removing the residue preceding Asp 4 has minimal effect upon the binding activity of NKA, the peptide from which GR64349 is derived:
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(Rovero, et al., page 266, Table 3).
In the above table, the R.P.A. experiment is the NK-2 system of interest (Rovero et al., page 265, col. 1, para. 1). Rovero demonstrates that the activity does not significantly change until the NKA peptide is reduced to residues 5-10, making residues 4-10 the critical residues. Residues 4-10 of NKA correspond to Asp4-Ser5-Phe6-Val7-Gly8-Leu9-Met10. (Deal et al., page 4195, Fig. 1).
Rovero also discloses the Nle substitution: “This study showed that the replacement of Met by the isosteric group Nle is quite well tolerated by the NK-2 receptor and therefore [Nle10]-NKA showed some selectivity. When made in the NKA (4-10), the same substitution brought to the of a fairly selective agonist for the NK-2 receptor, namely [Nle10]-NKA (4-10).” (Rovero et al., page 268, col. 1, para.1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to truncate peptide GR64349 disclosed by Thor as suggested by Rovero and make the Met to Nle substitution as described by Rovero to arrive at the claimed invention.
A person of ordinary skill in the art would have a reasonable expectation of success of truncating GR64349 as suggested by Rovero because of the data that shows that the truncated peptide should bind properly and that the Met to Nle substitution displays selectivity. A person of ordinary skill in the art would shorten the peptide to change the pharmacokinetics of the peptide or in this case, perhaps alter the polarity and modulate NK-2 receptor selectivity in order to reduce unwanted side effects or enable the usage of a lower dose. A person of ordinary skill in the art would make the Met to Nle to obtain the selectivity described by Rovero.
Consequently, claim 3 is obvious over Thor et al. in view of Rovero et al., as evidenced by Deal et al. and rejected.
Regarding claim 4, claim 1 is obvious as described above. Claim 4 further recites the peptide compound of claim 1, wherein Xaa1 is absent, Xaa3 is Lys, and B is Met-NH2, or a pharmaceutically acceptable salt thereof (Compound C; SEQ ID NO: 3).
The peptide GR64349 disclosed by Thor has Xaa1 as Lys, Xaa3 as Ser and B is Met-NH2. Thor also discloses SEQ ID NO: 1, which is “a peptide 7 amino acids in length corresponding to amino acids 4 through 10 of NKA, except that Ser at position 5 of NKA is replaced with Lys, Leu at position 9 is methylated at the nitrogen, and Met at position 10 is replaced with norleucine.” (Thor et al., col. 11, line 22).
However, Rovero discloses that removing the residue preceding Asp 4 has minimal effect upon the binding activity of NKA, the peptide from which GR64349 is derived:
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(Rovero, et al., page 266, Table 3).
In the above table, the R.P.A. experiment is the NK-2 system of interest (Rovero et al., page 265, col. 1, para. 1). Rovero demonstrates that the activity does not significantly change until the NKA peptide is reduced to residues 5-10, making residues 4-10 the critical residues. Residues 4-10 of NKA correspond to Asp4-Ser5-Phe6-Val7-Gly8-Leu9-Met10. (Deal et al., page 4195, Fig. 1).
Thor discloses the Ser5 to Lys5 substitution: “a peptide 7 amino acids in length corresponding to amino acids 4 through 10 of NKA, except that Ser at position 5 of NKA is replaced with Lys, Leu at position 9 is methylated at the nitrogen, and Met at position 10 is replaced with norleucine.” (Thor et al., col. 11, line 22).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to truncate peptide GR64349 disclosed by Thor as suggested by Rovero, to make the Ser to Lys substitution as described by Thor to arrive at the claimed invention.
A person of ordinary skill in the art would have a reasonable expectation of success of modifying GR64349 as suggested by Rovero and Thor because of the data that shows the efficacy of SEQ ID NO: 1 (Thor et al., col. 37, line 57). A person of ordinary skill in the art would shorten the peptide to change the pharmacokinetics of the peptide or in this case, perhaps alter the polarity and module NK-2 receptor selectivity in order to reduce unwanted side effects or enable the usage of a lower dose. A person of ordinary skill in the art would make the Ser to Lys substitution to obtain activity closer to the activity profile as described in Thor (Thor et al., Fig 3).
Consequently, claim 4 is obvious over Thor et al. in view of Rovero et al., as evidenced by Deal et al. and rejected.
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the peptide compound of claim 1, wherein Xaa1 is absent, Xaa3 is Lys, and B is Nle-NH2, or a pharmaceutically acceptable salt thereof (Compound D; SEQ ID NO: 4).
The peptide GR64349 disclosed by Thor has Xaa1 as Lys, Xaa3 as Ser and B is Met-NH2. Thor also discloses SEQ ID NO: 1, which is “a peptide 7 amino acids in length corresponding to amino acids 4 through 10 of NKA, except that Ser at position 5 of NKA is replaced with Lys, Leu at position 9 is methylated at the nitrogen, and Met at position 10 is replaced with norleucine.” (Thor et al., col. 11, line 22).
However, Rovero discloses that removing the residue preceding Asp 4 has minimal effect upon the binding activity of NKA, the peptide from which GR64349 is derived:
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(Rovero, et al., page 266, Table 3).
In the above table, the R.P.A. experiment is the NK-2 system of interest (Rovero et al., page 265, col. 1, para. 1). Rovero demonstrates that the activity does not significantly change until the NKA peptide is reduced to residues 5-10, making residues 4-10 the critical residues. Residues 4-10 of NKA correspond to Asp4-Ser5-Phe6-Val7-Gly8-Leu9-Met10. (Deal et al., page 4195, Fig. 1).
Thor discloses the Ser5 to Lys5 substitution: “a peptide 7 amino acids in length corresponding to amino acids 4 through 10 of NKA, except that Ser at position 5 of NKA is replaced with Lys, Leu at position 9 is methylated at the nitrogen, and Met at position 10 is replaced with norleucine.” (Thor et al., col. 11, line 22).
Rovero also discloses the Met to Nle substitution: “This study showed that the replacement of Met by the isosteric group Nle is quite well tolerated by the NK-2 receptor and therefore [Nle10]-NKA showed some selectivity. When made in the NKA (4-10), the same substitution brought to the of a fairly selective agonist for the NK-2 receptor, namely [Nle10]-NKA (4-10).” (Rovero et al., page 268, col. 1, para.1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to truncate peptide GR64349 disclosed by Thor as suggested by Rovero, to make the Ser to Lys substitution as described by Thor, and to make the Met to Ile substitution as described by Rovero to arrive at the claimed invention.
A person of ordinary skill in the art would have a reasonable expectation of success of modifying GR64349 as suggested by Rovero and Thor because of the data that shows the efficacy of SEQ ID NO: 1 (Thor et al., col. 37, line 57). A person of ordinary skill in the art would shorten the peptide to change the pharmacokinetics of the peptide or in this case, perhaps alter the polarity and module NK-2 receptor selectivity in order to reduce unwanted side effects or enable the usage of a lower dose. A person of ordinary skill in the art would make the Ser to Lys substitution to obtain activity closer to the activity profile as described in Thor (Thor et al., Fig 3). A person of ordinary skill in the art would make the Met to Nle to obtain the selectivity described by Rovero.
Consequently, claim 5 is obvious over Thor et al. in view of Rovero et al., as evidenced by Deal et al. and rejected.
Regarding claim 11, claim 1 is obvious as described above. Thor et al. discloses: “Methods, pharmaceutical formulations, and kits are provided for using neurokinin 2 receptor agonists to effectuate voluntary “on-demand” voiding of urine and feces in mammals who cannot void without external invasion of the bladder and bowel or those who void involuntarily (i.e., those having urinary and/or fecal incontinence). (Thor et al., Abstract). Consequently, the use claimed by claim 11 is disclosed by Thor and therefore claim 11 is obvious over Thor et al. in view of Rovero et al., as evidenced by Deal et al. and rejected.
Regarding claim 16, claim 11 is obvious as described above. Claim 16 recites; “The pharmaceutical composition of claim 11, wherein the compound has a selectivity for activation of human neurokinin 2 receptor (hNK2R) versus human neurokinin 1 receptor (hNK1R) of at least 20-fold, of at least 50-fold, of at least 100-fold, or of at least 200-fold.”
MPEP 2112.01(II) states: “"Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.” The structure of claim 16 is identical to that of claim 1.
Therefore, the recited properties are necessarily present and claim 16 is obvious over Thor et al. in view of Rovero et al., as evidenced by Deal et al. and rejected.
Regarding claim 17, claim 11 is obvious as described above. Thor et al. discloses:
“Voiding dysfunction is extremely prevalent in patients with spinal cord injury, spinabifida, multiple sclerosis, and other conditions involving spinal cord pathology” (Thor et al., col. 1, line 42).
Consequently, claim 17 is obvious over Thor et al. in view of Rovero et al., as evidenced by Deal et al. and rejected.
Regarding claim 22, claim 1 is obvious as described above. Thor et al. discloses: “In one embodiment of the presently disclosed subject matter, a method is provided for inducing one of urinary voiding and defecation in a mammal, which comprises administering on an as-needed basis to the mammal a therapeutically effective amount of an neurokinin 2 receptor (NK2R) agonist or a pharmaceutically acceptable salt thereof, wherein the NK2R agonist or the pharmaceutically acceptable salt thereof, has a rapid onset and a short duration of action, to induce one or both of the urinary voiding and defecation.” (Thor et al., col. 4, line 31).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the peptide disclosed by Thor to execute the method disclosed by Thor because GR64349 is disclosed to be a peptide agonist for NK2R. (Thor, et al., col. 11, line 39). A person would be motivated to use this peptide because it is disclosed to be an agonist for NK2R and NK2 receptor agonists are shown to have the claimed ability. (Thor et al., col. 37, line 42). Consequently, claim 22 is obvious over Thor et al. in view of Rovero et al., as evidenced by Deal et al. and rejected.
Regarding claim 23, claim 22 is obvious as described above. Thor et al. discloses: “The NK2R agonist, or the pharmaceutically acceptable salt thereof, can be formulated as an immediate release dosage form and the as-need administering can range from about 0 minutes to about 40 minutes prior to when the voiding and/or defecation is desired, from about 0 minutes to about 20 minutes prior to when the voiding and/or defecation is desired, or from about 0 minutes to about 5 minutes prior to when the voiding and/or defecation is desired.” (Thor et al. col. 16, line 63).
It would have been obvious for a person having ordinary skill in the art before the effective filing date of the claimed invention to use the immediate release dosage form in conjunction with the method of claim 22. A person of ordinary skill in the art would have a reasonable expectation of success because Thor discloses that: “These data demonstrate that DTI-100 contracts the bladder in a dose dependent manner and that the onset of action is rapid with a short duration of action. Furthermore, DTI-100 can be given repeatedly without significant loss of effect.” (Thor et al., col. 40, line 20). Consequently, claim 23 is obvious over Thor et al. in view of Rovero et al., as evidenced by Deal et al. and rejected.
Regarding claim 28, claim 22 is obvious as described above. Thor discloses: “Some other examples of drug delivery approaches focus on non-oral drug delivery, providing parenteral, transmucosal, and topical delivery of proteins, peptides, and small molecules.” (Thor et al., col. 32, line 16). Consequently, claim 28 is obvious over Thor et al. in view of Rovero et al., as evidenced by Deal et al. and rejected.
Claims 6 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Thor et al. (US 10,086,034, filed 1/27/2016) in view of Rovero et al. (Rovero, et al. Neuropeptides 13.4: 263-270 (1989)) as evidenced by Deal et al. (Deal, et al. Journal of medicinal chemistry 35.22: 4195-4204 (1992)) as applied to claim 1 above, further in view of Trivedi et al. (Trivedi, et al. Protein Science 29.11 : 2150-2163 2020)).
Regarding claim 6, claim 1 is obvious as described above. Claim 6 further recites the peptide compound of claim 1, wherein Xaa1 is absent, Xaa3 is Arg, and B is Met-NH2, or a pharmaceutically acceptable salt thereof (Compound E; SEQ ID NO: 5).
The peptide GR64349 disclosed by Thor has Xaa1 as Lys, Xaa3 as Ser and B is Met-NH2. Thor also discloses SEQ ID NO: 1, which is “a peptide 7 amino acids in length corresponding to amino acids 4 through 10 of NKA, except that Ser at position 5 of NKA is replaced with Lys, Leu at position 9 is methylated at the nitrogen, and Met at position 10 is replaced with norleucine.” (Thor et al., col. 11, line 22).
However, Rovero discloses that removing the residue preceding Asp 4 has minimal effect upon the binding activity of NKA, the peptide from which GR64349 is derived:
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(Rovero, et al., page 266, Table 3).
In the above table, the R.P.A. experiment is the NK-2 system of interest (Rovero et al., page 265, col. 1, para. 1). Rovero demonstrates that the activity does not significantly change until the NKA peptide is reduced to residues 5-10, making residues 4-10 the critical residues. Residues 4-10 of NKA correspond to Asp4-Ser5-Phe6-Val7-Gly8-Leu9-Met10. (Deal et al., page 4195, Fig. 1).
Thor discloses the Ser5 to Lys5 substitution: “a peptide 7 amino acids in length corresponding to amino acids 4 through 10 of NKA, except that Ser at position 5 of NKA is replaced with Lys, Leu at position 9 is methylated at the nitrogen, and Met at position 10 is replaced with norleucine.” (Thor et al., col. 11, line 22).
Furthermore, Trivedi discloses that according to both BLOSUM62 and GPCRtm substitution matrices, a lysine to arginine substitution is well-tolerated (Trivedi et al., page 2157, Table 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to truncate peptide GR64349 disclosed by Thor as suggested by Rovero, to make the Ser to Lys substitution as described by Thor and then implement a Lys to Arg substitution as described by Trivedi to arrive at the claimed invention.
A person of ordinary skill in the art would have a reasonable expectation of success of modifying GR64349 as suggested by Rovero and Thor because of the data that shows the efficacy of SEQ ID NO: 1 (Thor et al., col. 37, line 57). Also, Trivedi shows that a lysine to arginine substitution has a reasonable expectation of success based on the matrix substitution scores. A person of ordinary skill in the art would shorten the peptide to change the pharmacokinetics of the peptide or in this case, perhaps alter the polarity and module NK-2 receptor selectivity in order to reduce unwanted side effects or enable the usage of a lower dose. A person of ordinary skill in the art would make the Ser to Lys substitution to obtain activity closer to the activity profile as described in Thor (Thor et al., Fig 3). A person of ordinary skill in the art would find it obvious to try a lysine to arginine substitution based off the Trivedi matrix in order to see if the properties can be further improved.
Consequently, claim 6 is obvious over Thor et al. in view of Rovero et al., as evidenced by Deal et al. as applied to claim 1 above, further in view of Trivedi et al. and rejected.
Regarding claim 7, claim 1 is obvious as described above. Claim 7 further recites the peptide compound of claim 1, wherein Xaa1 is absent, Xaa3 is Lys, and B is Met-NH2, or a pharmaceutically acceptable salt thereof (Compound F; SEQ ID NO: 6).
The peptide GR64349 disclosed by Thor has Xaa1 as Lys, Xaa3 as Ser and B is Met-NH2. Thor also discloses SEQ ID NO: 1, which is “a peptide 7 amino acids in length corresponding to amino acids 4 through 10 of NKA, except that Ser at position 5 of NKA is replaced with Lys, Leu at position 9 is methylated at the nitrogen, and Met at position 10 is replaced with norleucine.” (Thor et al., col. 11, line 22).
However, Rovero discloses that removing the residue preceding Asp 4 has minimal effect upon the binding activity of NKA, the peptide from which GR64349 is derived:
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(Rovero, et al., page 266, Table 3).
In the above table, the R.P.A. experiment is the NK-2 system of interest (Rovero et al., page 265, col. 1, para. 1). Rovero demonstrates that the activity does not significantly change until the NKA peptide is reduced to residues 5-10, making residues 4-10 the critical residues. Residues 4-10 of NKA correspond to Asp4-Ser5-Phe6-Val7-Gly8-Leu9-Met10. (Deal et al., page 4195, Fig. 1).
Thor discloses the Ser5 to Lys5 substitution: “a peptide 7 amino acids in length corresponding to amino acids 4 through 10 of NKA, except that Ser at position 5 of NKA is replaced with Lys, Leu at position 9 is methylated at the nitrogen, and Met at position 10 is replaced with norleucine.” (Thor et al., col. 11, line 22).
Rovero also discloses the Met to Nle substitution: “This study showed that the replacement of Met by the isosteric group Nle is quite well tolerated by the NK-2 receptor and therefore [Nle10]-NKA showed some selectivity. When made in the NKA (4-10), the same substitution brought to the of a fairly selective agonist for the NK-2 receptor, namely [Nle10]-NKA (4-10).” (Rovero et al., page 268, col. 1, para.1).
Furthermore, Trivedi discloses that according to both BLOSUM62 and GPCRtm substitution matrices, a lysine to arginine substitution is well-tolerated (Trivedi et al., page 2157, Table 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to truncate peptide GR64349 disclosed by Thor as suggested by Rovero, to make the Ser to Lys substitution as described by Thor, and to make the Met to Ile substitution as described by Rovero to arrive at the claimed invention.
A person of ordinary skill in the art would have a reasonable expectation of success of modifying GR64349 as suggested by Rovero and Thor because of the data that shows the efficacy of SEQ ID NO: 1 (Thor et al., col. 37, line 57). Also, Trivedi shows that a lysine to arginine substitution has a reasonable expectation of success based on the matrix substitution scores .
A person of ordinary skill in the art would shorten the peptide to change the pharmacokinetics of the peptide or in this case, perhaps alter the polarity and module NK-2 receptor selectivity in order to reduce unwanted side effects or enable the usage of a lower dose. A person of ordinary skill in the art would make the Ser to Lys substitution to obtain activity closer to the activity profile as described in Thor (Thor et al., Fig 3).. A person of ordinary skill in the art would make the Met to Nle to obtain the selectivity described by Rovero. A person of ordinary skill in the art would find it obvious to try a lysine to arginine substitution based off the Trivedi matrix in order to see if the properties can be further improved.
Consequently, claim 7 is obvious over Thor et al. in view of Rovero et al., as evidenced by Deal et al. as applied to claim 1 above, further in view of Trivedi et al. and rejected.
Claims 18 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Thor et al. (US 10,086,034, filed 1/27/2016) in view of Rovero et al. (Rovero, et al. Neuropeptides 13.4: 263-270 (1989)) as evidenced by Deal et al. (Deal, et al. Journal of medicinal chemistry 35.22: 4195-4204 (1992)) as applied to claim 11 above, further in view of Muheem et al. (Muheem, et al. Saudi Pharmaceutical Journal 24.4: 413-428 (2016)).
Regarding claim 18, claim 11 is obvious as described above. Compound C is obvious as described above. Claim 18 further recites: “… the composition is formulated for compatibility with a hydrophilic peptide compound in an aqueous solution.”
Muheem discloses that “The two important approaches for formulation of protein and peptides by oral route include: use of absorption enhancers and enzymatic inhibitor. Being charged, large in size and hydrophilic, proteins and peptides are notoriously poor permeators (and thus exhibit poor oral bioavailability per se).” (Muheem et al., page 417, col. 2, para. 3). Consequently, it would been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine Compound C of Thor and Rovero and utilize the formulation strategies of Muheem to address the issues of permeation and bioavailability to arrive at the claimed invention. A person of ordinary skill in the art would be motivated to do this in order to address the shortcomings disclosed by Muheem. Therefore, claim 18 is obvious over Thor et al. in view of Rovero et al., further in view of Muheem et al. and rejected.
Regarding claim 24, claim 4 is obvious as described above. Furthermore, claim 18 is obvious as described above.
Thor et al. discloses: “In one embodiment of the presently disclosed subject matter, a method is provided for treating one of urinary voiding and defecation dysfunction in a mammal in need of treatment, which comprises administering on an as-needed basis to the mammal a therapeutically effective amount of an neurokinin 2 receptor (NK2R) agonist or a pharmaceutically acceptable salt thereof, wherein the NK2R agonist or the pharmaceutically acceptable salt thereof, has a rapid onset and a short duration of action, to induce the one or both of urinary voiding and defecation.” (Thor et al., col. 4, line 13).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the composition of claims 4 and 18 to execute the method disclosed by Thor. A person of ordinary skill in the art would be motivated to use these compositions in an aqueous system to overcome the issues disclosed by Muheem above. A person of ordinary skill in the art would have a reasonable expectation of success because Thor discloses the activity of NK2 agonists (Thor et al., col. 37, line 30). Consequently, claim 24 is obvious over Thor et al. in view of Rovero et al. as evidenced by Deal et al. (Deal, et al. Journal of medicinal chemistry 35.22: 4195-4204 (1992)) as applied to claim 11 above, further in view of Muheem et al. and rejected.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Thor et al. (US 10,086,034, filed 1/27/2016) in view of Rovero et al. (Rovero, et al. Neuropeptides 13.4: 263-270 (1989)) as evidenced by Deal et al. (Deal, et al. Journal of medicinal chemistry 35.22: 4195-4204 (1992)) as applied to claim 11, further in view of Surasarang et al. (Surasarang, et al. Drug development and industrial pharmacy 44.2: 184-198 (2018)).
Regarding claim 19, claim 11 is obvious as described above. Compound C is obvious as described above. Claim 19 further recites: “… wherein the composition comprises the peptide compound C, D, E, F, or G formulated for administering in an aqueous isotonic solution.”
Surasarang discloses that “It is important to obtain isotonic solution after reconstitution of the lyophilized formulations. The non-isotonic solutions can cause the release of histamine, which resulted from changing of the osmotic load around mast cells [47]. The release of histamine is responsible for bronchoconstriction .” (Surasarang et al., page 188, col. 1, para. 3).
Consequently, it would been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine Compound C of Thor and Rovero and utilize the formulation strategies of Surasarang to address the issues of undesirable release of histimine. A person of ordinary skill in the art would be motivated to do this in order to address the issue of release of histamine as disclosed by Surasarang. Therefore, claim 19 is obvious over Thor et al. in view of Rovero et al. as evidenced by Deal et al. (Deal, et al. Journal of medicinal chemistry 35.22: 4195-4204 (1992)) as applied to claim 11 above, further in view of Surasarang et al. and rejected.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Thor et al. (US 10,086,034, filed 1/27/2016) in view of Rovero et al. (Rovero, et al. Neuropeptides 13.4: 263-270 (1989)) as evidenced by Deal et al. (Deal, et al. Journal of medicinal chemistry 35.22: 4195-4204 (1992)) as applied to claim 11, further in view of Akanbi, et al. (Akanbi, et al. Colloids and surfaces B: Biointerfaces 75.2: 526-531 (2010)).
Regarding claim 20, claim 11 is obvious as described above. Compound A is obvious as described above. Claim 19 further recites: “…wherein the composition comprises the peptide compound A or B and the composition is formulated for compatibility with a hydrophobic peptide compound.”.
Akanbi discloses that: “The poor water solubility of many drugs requires a specific formulation to achieve a sufficient bioavailability after oral administration. Suspensions of small drug particles can be used to improve the bioavailability. We here show that the fungal hydrophobin SC3 can be used to make suspensions of water insoluble drugs.” (Akanbi, et al., page 526, Abstract).
Consequently, it would been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine Compound A of Thor and Rovero and utilize the formulation strategies of Akanbi to address the issues of delivery of hydrophobic peptides. A person of ordinary skill in the art would be motivated to do this in order to address the issue of delivery of hydrophobic peptides as disclosed by Surasarang. Therefore, claim 20 is obvious over Thor et al. in view of Rovero et al., as evidenced by Deal et al. as evidenced by Deal et al. (Deal, et al. Journal of medicinal chemistry 35.22: 4195-4204 (1992)) as applied to claim 11 above, further in view of Akanbi et al. and rejected.
Claims 1, 2, 4, 11, 16, 17, 22, 23, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Thor et al. (US 10,086,034, filed 1/27/2016) in view of Deal et al. (Deal, et al. Journal of medicinal chemistry 35.22: 4195-4204 (1992)).
Regarding claim 1, claim 1 recites:
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Thor discloses SEQ ID NO: 5, Asp4-Ser5-Phe6-Val7-Gly8-Leu9-Met10-NH2, which is same sequence claimed by Applicant claim 1 without the γ-lactam constraint at position 9 (Thor et al., col. 14, line 49).
However, Deal discloses that: “With particular relevance to this work, it has been reported that replacement of the Gly9 residue in SP-related peptides by Pro enhances NK-1 receptor selectivity,5 whereas introduction of D-Pro or an R-γ-lactam constraint at this position enhances NK-2 receptor selectivity.6” (Deal et al., page 4195, col. 1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add a gamma lactam constraint as suggested by Deal to SEQ ID NO: 5 of Thor to arrive at the claimed invention.
A person of ordinary skill in the art would have a reasonable expectation of success of adding the gamma lactam to SEQ ID NO: 5 of Thor because Deal discloses that it enhances NK-2 receptor selectivity as described above. A person of ordinary skill in the art would seek to enhance NK-2 receptor selectivity in order to reduce unwanted side effects or enable the usage of a lower dose.
Consequently, claim 1 is obvious over Thor et al. in view of Deal et al. and rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites the peptide compound of claim 1, wherein Xaa1 is absent, Xaa3 is Ser, and B is Met-NH2, or a pharmaceutically acceptable salt thereof (Compound A; SEQ ID NO: 1).
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further limits Xaa3 to Ser and B to Met-NH2. In Thor, Xaa3 is Ser and B is Met-NH2.
Consequently, claim 2 is obvious over Thor et al. in view of Deal et al. and rejected.
Regarding claim 4, claim 1 is obvious as described above. Claim 4 further recites the peptide compound of claim 1, wherein Xaa1 is absent, Xaa3 is Lys, and B is Met-NH2, or a pharmaceutically acceptable salt thereof (Compound C; SEQ ID NO: 3).
Thor discloses SEQ ID NO: 5, Asp4-Ser5-Phe6-Val7-Gly8-Leu9-Met10-NH2, which is same sequence claimed by Applicant claim 2 without the γ-lactam constraint at position 9 (Thor et al., col. 14, line 49) and with Ser in place of Lys.
Deal discloses that: “With particular relevance to this work, it has been reported that replacement of the Gly9 residue in SP-related peptides by Pro enhances NK-1 receptor selectivity,5 whereas introduction of D-Pro or an R-γ-lactam constraint at this position enhances NK-2 receptor selectivity.6” (Deal et al., page 4195, col. 1, para. 1).
Thor discloses SEQ ID NO: 1, which is “a peptide 7 amino acids in length corresponding to amino acids 4 through 10 of NKA, except that Ser at position 5 of NKA is replaced with Lys, Leu at position 9 is methylated at the nitrogen, and Met at position 10 is replaced with norleucine.” (Thor et al., col. 11, line 22).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add a gamma lactam constraint as suggested by Deal to SEQ ID NO: 5 of Thor and make the Ser to Lys substitution as disclosed by Thor.
A person of ordinary skill in the art would have a reasonable expectation of success of adding the gamma lactam to SEQ ID NO: 5 of Thor because Deal discloses that it enhances NK-2 receptor selectivity as described above and Thor discloses that a Ser5 to Lys5 substitution results in a successful peptide in the case of SEQ ID NO: 1. (Thor et al., Figure 3) A person of ordinary skill in the art would seek to enhance NK-2 receptor selectivity in order to reduce unwanted side effects or enable the usage of a lower dose and modulate peptide activity to be closer to that if SEQ ID NO: 1 of Thor.
Consequently, claim 4 is obvious over Thor et al. in view of Deal et al. and rejected.
Regarding claim 11, claim 1 is obvious as described above. Thor et al. discloses: “Methods, pharmaceutical formulations, and kits are provided for using neurokinin 2 receptor agonists to effectuate voluntary “on-demand” voiding of urine and feces in mammals who cannot void without external invasion of the bladder and bowel or those who void involuntarily (i.e., those having urinary and/or fecal incontinence). (Thor et al., Abstract). Consequently, the use claimed by claim 11 is disclosed by Thor and therefore claim 11 is obvious over Thor et al. in view of Deal et al. and rejected.
Regarding claim 16, claim 11 is obvious as described above. Claim 16 recites; “The pharmaceutical composition of claim 11, wherein the compound has a selectivity for activation of human neurokinin 2 receptor (hNK2R) versus human neurokinin 1 receptor (hNK1R) of at least 20-fold, of at least 50-fold, of at least 100-fold, or of at least 200-fold.”
MPEP 2112.01(II) states: “"Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.” The structure of claim 16 is identical to that of claim 1.
Therefore, the recited properties are necessarily present and claim 16 is obvious over Thor et al. in view of Deal et al. and rejected.
Regarding claim 17, claim 11 is obvious as described above. Thor et al. discloses:
“Voiding dysfunction is extremely prevalent in patients with spinal cord injury, spinabifida, multiple sclerosis, and other conditions involving spinal cord pathology” (Thor et al., col. 1, line 42).
Consequently, claim 17 is obvious over Thor et al. in view of Deal et al. and rejected.
Regarding claim 22, claim 1 is anticipated as described above. Thor et al. discloses: “In one embodiment of the presently disclosed subject matter, a method is provided for inducing one of urinary voiding and defecation in a mammal, which comprises administering on an as-needed basis to the mammal a therapeutically effective amount of an neurokinin 2 receptor (NK2R) agonist or a pharmaceutically acceptable salt thereof, wherein the NK2R agonist or the pharmaceutically acceptable salt thereof, has a rapid onset and a short duration of action, to induce one or both of the urinary voiding and defecation.” (Thor et al., col. 4, line 31).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the peptide disclosed by Thor to execute the method disclosed by Thor because GR64349 is disclosed to be a peptide agonist for NK2R. (Thor, et al., col. 11, line 39). A person would be motivated to use this peptide because it is disclosed to be an agonist for NK2R and NK2 receptor agonists are shown to have the claimed ability. (Thor et al., col. 37, line 42). Consequently, claim 22 is obvious over Thor et al. in view of Deal et al. and rejected.
Regarding claim 23, claim 22 is obvious as described above. Thor et al. discloses: “The NK2R agonist, or the pharmaceutically acceptable salt thereof, can be formulated as an immediate release dosage form and the as-need administering can range from about 0 minutes to about 40 minutes prior to when the voiding and/or defecation is desired, from about 0 minutes to about 20 minutes prior to when the voiding and/or defecation is desired, or from about 0 minutes to about 5 minutes prior to when the voiding and/or defecation is desired.” (Thor et al. col. 16, line 63).
It would have been obvious for a person having ordinary skill in the art before the effective filing date of the claimed invention to use the immediate release dosage form in conjunction with the method of claim 22. A person of ordinary skill in the art would have a reasonable expectation of success because Thor discloses that: “These data demonstrate that DTI-100 contracts the bladder in a dose dependent manner and that the onset of action is rapid with a short duration of action. Furthermore, DTI-100 can be given repeatedly without significant loss of effect.” (Thor et al., col. 40, line 20). Consequently, claim 23 is obvious over Thor et al. in view of Deal et al. and rejected.
Regarding claim 28, claim 22 is obvious as described above. Thor discloses: “Some other examples of drug delivery approaches focus on non-oral drug delivery, providing parenteral, transmucosal, and topical delivery of proteins, peptides, and small molecules.” (Thor et al., col. 32, line 16). Consequently, claim 28 is obvious over Thor et al. in view of Deal et al. and rejected.
Claims 3 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Thor et al. (US 10,086,034, filed 1/27/2016) in view of Deal et al. (Deal, et al. Journal of medicinal chemistry 35.22: 4195-4204 (1992)) as applied to claim 1, and further in view of Rovero et al. (Rovero, et al. Neuropeptides 13.4: 263-270 (1989).
Regarding claim 3, claim 1 is obvious as described above. Claim 3 further recites the peptide compound of claim 1, wherein Xaa1 is absent, Xaa3 is Ser, and B is Nle-NH2, or a pharmaceutically acceptable salt thereof (Compound B; SEQ ID NO: 2).
Thor discloses SEQ ID NO: 5, Asp4-Ser5-Phe6-Val7-Gly8-Leu9-Met10-NH2, which is same sequence claimed by Applicant claim 2 without the γ-lactam constraint at position 9 (Thor et al., col. 14, line 49).
Deal discloses that: “With particular relevance to this work, it has been reported that replacement of the Gly9 residue in SP-related peptides by Pro enhances NK-1 receptor selectivity,5 whereas introduction of D-Pro or an R-γ-lactam constraint at this position enhances NK-2 receptor selectivity.6” (Deal et al., page 4195, col. 1, para. 1).
Rovero discloses the Nle substitution: “This study showed that the replacement of Met by the isosteric group Nle is quite well tolerated by the NK-2 receptor and therefore [Nle10]-NKA showed some selectivity. When made in the NKA (4-10), the same substitution brought to the of a fairly selective agonist for the NK-2 receptor, namely [Nle10]-NKA (4-10).” (Rovero et al., page 268, col. 1, para.1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add a gamma lactam constraint as suggested by Deal to SEQ ID NO: 5 of Thor and make the Met to Nle substitution as described by Rovero to arrive at the claimed invention.
A person of ordinary skill in the art would have a reasonable expectation of success of adding the gamma lactam to SEQ ID NO: 5 of Thor because Deal discloses that it enhances NK-2 receptor selectivity as described above and Rovero discloses that a Met to Nle substitution successfully modulates selectivity of the peptide. A person of ordinary skill in the art would seek to enhance NK-2 receptor selectivity in order to reduce unwanted side effects or enable the usage of a lower dose.
Consequently, claim 3 is obvious over Thor et al. in view of Deal et al. and Rovero et al. rejected.
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the peptide compound of claim 1, wherein Xaa1 is absent, Xaa3 is Lys, and B is Nle-NH2, or a pharmaceutically acceptable salt thereof (Compound B; SEQ ID NO: 2).
Thor discloses SEQ ID NO: 5, Asp4-Ser5-Phe6-Val7-Gly8-Leu9-Met10-NH2, which is same sequence claimed by Applicant claim 2 without the γ-lactam constraint at position 9 (Thor et al., col. 14, line 49).
Deal discloses that: “With particular relevance to this work, it has been reported that replacement of the Gly9 residue in SP-related peptides by Pro enhances NK-1 receptor selectivity,5 whereas introduction of D-Pro or an R-γ-lactam constraint at this position enhances NK-2 receptor selectivity.6” (Deal et al., page 4195, col. 1, para. 1).
Rovero discloses the Nle substitution: “This study showed that the replacement of Met by the isosteric group Nle is quite well tolerated by the NK-2 receptor and therefore [Nle10]-NKA showed some selectivity. When made in the NKA (4-10), the same substitution brought to the of a fairly selective agonist for the NK-2 receptor, namely [Nle10]-NKA (4-10).” (Rovero et al., page 268, col. 1, para.1).
Thor also discloses SEQ ID NO: 1, which is “a peptide 7 amino acids in length corresponding to amino acids 4 through 10 of NKA, except that Ser at position 5 of NKA is replaced with Lys, Leu at position 9 is methylated at the nitrogen, and Met at position 10 is replaced with norleucine.” (Thor et al., col. 11, line 22).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add a gamma lactam constraint as suggested by Deal to SEQ ID NO: 5 of Thor and make the Met to Nle substitution as described by Rovero and the Ser to Lys substitution as described by Thor to arrive at the claimed invention.
A person of ordinary skill in the art would have a reasonable expectation of success of adding the gamma lactam to SEQ ID NO: 5 of Thor because Deal discloses that it enhances NK-2 receptor selectivity as described above and Rovero discloses that a Met to Nle substitution successfully modulates selectivity of the peptide. Thor also shows that Ser to Lys results in an efficacious peptide with SEQ ID NO: 1 (Thor et al., Figure 3). A person of ordinary skill in the art would seek to enhance or modulate NK-2 receptor selectivity in order to reduce unwanted side effects or enable the usage of a lower dose.
Consequently, claim 5 is obvious over Thor et al. in view of Deal et al. and Rovero et al. rejected.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Thor et al. (US 10,086,034, filed 1/27/2016) in view of Deal et al. (Deal, et al. Journal of medicinal chemistry 35.22: 4195-4204 (1992)) as applied to claim 1, further in view of Trivedi et al. (Trivedi, et al. Protein Science 29.11 : 2150-2163 2020)).
Regarding claim 6, claim 1 is obvious as described above. Claim 6 further recites the peptide compound of claim 1, wherein Xaa1 is absent, Xaa3 is Arg, and B is Met-NH2, or a pharmaceutically acceptable salt thereof (Compound E; SEQ ID NO: 5).
Thor discloses SEQ ID NO: 5, Asp4-Ser5-Phe6-Val7-Gly8-Leu9-Met10-NH2, which is same sequence claimed by Applicant claim 2 without the γ-lactam constraint at position 9 (Thor et al., col. 14, line 49) and with Ser in place of Lys.
Deal discloses that: “With particular relevance to this work, it has been reported that replacement of the Gly9 residue in SP-related peptides by Pro enhances NK-1 receptor selectivity,5 whereas introduction of D-Pro or an R-γ-lactam constraint at this position enhances NK-2 receptor selectivity.6” (Deal et al., page 4195, col. 1, para. 1).
Thor discloses SEQ ID NO: 1, which is “a peptide 7 amino acids in length corresponding to amino acids 4 through 10 of NKA, except that Ser at position 5 of NKA is replaced with Lys, Leu at position 9 is methylated at the nitrogen, and Met at position 10 is replaced with norleucine.” (Thor et al., col. 11, line 22).
Furthermore, Trivedi discloses that according to both BLOSUM62 and GPCRtm substitution matrices, a lysine to arginine substitution is well-tolerated (Trivedi et al., page 2157, Table 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add a gamma lactam constraint as suggested by Deal to SEQ ID NO: 5 of Thor and make the Ser to Lys substitution as disclosed by Thor.
A person of ordinary skill in the art would have a reasonable expectation of success of adding the gamma lactam to SEQ ID NO: 5 of Thor because Deal discloses that it enhances NK-2 receptor selectivity as described above and Thor discloses that a Ser5 to Lys5 substitution results in a successful peptide in the case of SEQ ID NO: 1. (Thor et al., Figure 3). Also, Trivedi shows that a lysine to arginine substitution has a reasonable expectation of success based on the matrix substitution scores.
A person of ordinary skill in the art would seek to enhance NK-2 receptor selectivity in order to reduce unwanted side effects or enable the usage of a lower dose and modulate peptide activity to be closer to that if SEQ ID NO: 1 of Thor (Thor et al., Figure 3). A person of ordinary skill in the art would find it obvious to try a lysine to arginine substitution based off the Trivedi matrix in order to see if the properties can be further improved.
Consequently, claim 6 is obvious over Thor et al. in view of Deal et al., further in view of Trivedi et al. and rejected.
Claims 7 is rejected under 35 U.S.C. 103 as being unpatentable over Thor et al. (US 10,086,034, filed 1/27/2016) in view of Deal et al. (Deal, et al. Journal of medicinal chemistry 35.22: 4195-4204 (1992)) as applied to claim 1, further in view of Rovero et al. (Rovero, et al. Neuropeptides 13.4: 263-270 (1989) and Trivedi et al. (Trivedi, et al. Protein Science 29.11 : 2150-2163 2020)).
Regarding claim 7, claim 1 is obvious as described above. Claim 7 further recites the peptide compound of claim 1, wherein Xaa1 is absent, Xaa3 is Arg, and B is Nle-NH2, or a pharmaceutically acceptable salt thereof (Compound F; SEQ ID NO: 6).
Thor discloses SEQ ID NO: 5, Asp4-Ser5-Phe6-Val7-Gly8-Leu9-Met10-NH2, which is same sequence claimed by Applicant claim 2 without the γ-lactam constraint at position 9 (Thor et al., col. 14, line 49).
Deal discloses that: “With particular relevance to this work, it has been reported that replacement of the Gly9 residue in SP-related peptides by Pro enhances NK-1 receptor selectivity,5 whereas introduction of D-Pro or an R-γ-lactam constraint at this position enhances NK-2 receptor selectivity.6” (Deal et al., page 4195, col. 1, para. 1).
Rovero discloses the Nle substitution: “This study showed that the replacement of Met by the isosteric group Nle is quite well tolerated by the NK-2 receptor and therefore [Nle10]-NKA showed some selectivity. When made in the NKA (4-10), the same substitution brought to the of a fairly selective agonist for the NK-2 receptor, namely [Nle10]-NKA (4-10).” (Rovero et al., page 268, col. 1, para.1).
Thor also discloses SEQ ID NO: 1, which is “a peptide 7 amino acids in length corresponding to amino acids 4 through 10 of NKA, except that Ser at position 5 of NKA is replaced with Lys, Leu at position 9 is methylated at the nitrogen, and Met at position 10 is replaced with norleucine.” (Thor et al., col. 11, line 22).
Furthermore, Trivedi discloses that according to both BLOSUM62 and GPCRtm substitution matrices, a lysine to arginine substitution is well-tolerated (Trivedi et al., page 2157, Table 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add a gamma lactam constraint as suggested by Deal to SEQ ID NO: 5 of Thor and make the Met to Nle substitution as described by Rovero and the Ser to Lys substitution as described by Thor to arrive at the claimed invention.
A person of ordinary skill in the art would have a reasonable expectation of success of adding the gamma lactam to SEQ ID NO: 5 of Thor because Deal discloses that it enhances NK-2 receptor selectivity as described above and Rovero discloses that a Met to Nle substitution successfully modulates selectivity of the peptide. Thor also shows that Ser to Lys results in an efficacious peptide with SEQ ID NO: 1 (Thor et al., Figure 3). Also, Trivedi shows that a lysine to arginine substitution has a reasonable expectation of success based on the matrix substitution scores.
A person of ordinary skill in the art would seek to enhance or modulate NK-2 receptor selectivity in order to reduce unwanted side effects or enable the usage of a lower dose. A person of ordinary skill in the art would also find it obvious to try a lysine to arginine substitution based off the Trivedi matrix in order to see if the properties can be further improved.
Consequently, claim 7 is obvious over Thor et al. in view of Deal et al. as applied to claim 1 above, further in view of Rovero et al. and Trivedi et al. and rejected.
.
Claims 18 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Thor et al. (US 10,086,034, filed 1/27/2016) in view of Deal et al. (Deal, et al. Journal of medicinal chemistry 35.22: 4195-4204 (1992)) as applied to claims 4 and 11, further in view of Rovero et al. (Rovero, et al. Neuropeptides 13.4: 263-270 (1989) and Muheem et al. (Muheem, et al. Saudi Pharmaceutical Journal 24.4: 413-428 (2016)).
Regarding claim 18, claim 11 is obvious as described above. Compound C is obvious as described above.
Claim 18 further recites: “… the composition is formulated for compatibility with a hydrophilic peptide compound in an aqueous solution.”
Muheem discloses that “The two important approaches for formulation of protein and peptides by oral route include: use of absorption enhancers and enzymatic inhibitor. Being charged, large in size and hydrophilic, proteins and peptides are notoriously poor permeators (and thus exhibit poor oral bioavailability per se).” (Muheem et al., page 417, col. 2, para. 3). Consequently, it would been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine Compound C of Thor and Deal and utilize the formulation strategies of Muheem to address the issues of permeation and bioavailability to arrive at the claimed invention. A person of ordinary skill in the art would be motivated to do this in order to address the shortcomings disclosed by Muheem. Therefore, claim 18 is obvious over Thor et al. in view of Deal et al. as applied to claim 11 above, and further in view of Muheem et al. and rejected.
Regarding claim 24, claim 4 is obvious as described above. Furthermore, claim 18 is obvious as described above.
Thor et al. discloses: “In one embodiment of the presently disclosed subject matter, a method is provided for treating one of urinary voiding and defecation dysfunction in a mammal in need of treatment, which comprises administering on an as-needed basis to the mammal a therapeutically effective amount of an neurokinin 2 receptor (NK2R) agonist or a pharmaceutically acceptable salt thereof, wherein the NK2R agonist or the pharmaceutically acceptable salt thereof, has a rapid onset and a short duration of action, to induce the one or both of urinary voiding and defecation.” (Thor et al., col. 4, line 13).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the composition of claims 4 and 18 to execute the method disclosed by Thor. A person of ordinary skill in the art would be motivated to use these compositions in an aqueous system to overcome the issues disclosed by Muheem above. A person of ordinary skill in the art would have a reasonable expectation of success because Thor discloses the activity of NK2 agonists (Thor et al., col. 37, line 30). Consequently, claim 24 is obvious over Thor et al. in view of Deal et al. as applied to claim 11 above, and further in view of Muheem et al. and rejected.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Thor et al. (US 10,086,034, filed 1/27/2016) in view of Deal et al. (Deal, et al. Journal of medicinal chemistry 35.22: 4195-4204 (1992)) as applied to claim 11, further in view of Surasarang et al. (Surasarang, et al. Drug development and industrial pharmacy 44.2: 184-198 (2018)).
Regarding claim 19, claim 11 is obvious as described above. Compound C is obvious as described above. Claim 19 further recites: “… wherein the composition comprises the peptide compound C, D, E, F, or G formulated for administering in an aqueous isotonic solution.”
Surasarang discloses that “It is important to obtain isotonic solution after reconstitution of the lyophilized formulations. The non-isotonic solutions can cause the release of histamine, which resulted from changing of the osmotic load around mast cells [47]. The release of histamine is responsible for bronchoconstriction .” (Surasarang et al., page 188, col. 1, para. 3). Consequently, it would been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine Compound C of Thor and Deal and utilize the formulation strategies of Surasarang to address the issues of undesirable release of histimine. A person of ordinary skill in the art would be motivated to do this in order to address the issue of release of histimine as disclosed by Surasarang. Therefore, claim 19 is obvious over Thor et al. and Deal et al. as applied to claim 11, further in view of Surasarang et al. and rejected.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Thor et al. (US 10,086,034, filed 1/27/2016) in view of Deal et al. (Deal, et al. Journal of medicinal chemistry 35.22: 4195-4204 (1992)) as applied to claim 11, further in view of Akanbi, et al. (Akanbi, et al. Colloids and surfaces B: Biointerfaces 75.2: 526-531 (2010)).
Regarding claim 20, claim 11 is obvious as described above. Compound A is obvious as described above. Claim 19 further recites: “…wherein the composition comprises the peptide compound A or B and the composition is formulated for compatibility with a hydrophobic peptide compound.”.
Akanbi discloses that: “The poor water solubility of many drugs requires a specific formulation to achieve a sufficient bioavailability after oral administration. Suspensions of small drug particles can be used to improve the bioavailability. We here show that the fungal hydrophobin SC3 can be used to make suspensions of water insoluble drugs.” (Akanbi, et al., page 526, Abstract).
Consequently, it would been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine Compound A of Thor and Rovero and utilize the formulation strategies of Akanbi to address the issues of delivery of hydrophobic peptides. A person of ordinary skill in the art would be motivated to do this in order to address the issue of delivery of hydrophobic peptides as disclosed by Surasarang. Therefore, claim 20 is obvious over Thor et al. as evidenced by Deal et al., further in view of Akanbi et al. and rejected.
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Thor et al. (US 10,086,034, filed 1/27/2016), in view of Surasarang et al. (Surasarang, et al. Drug development and industrial pharmacy 44.2: 184-198 (2018)).
Regarding claim 25, claim 22 is obvious as described above.
Surasarang discloses that “It is important to obtain isotonic solution after reconstitution of the lyophilized formulations. The non-isotonic solutions can cause the release of histamine, which resulted from changing of the osmotic load around mast cells [47]. The release of histamine is responsible for bronchoconstriction .” (Surasarang et al., page 188, col. 1, para. 3).
Consequently, it would been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of Thor with the isotonic composition of Surasarang to address the issues of undesirable release of histamine. A person of ordinary skill in the art would be motivated to do this in order to address the issue of release of histamine as disclosed by Surasarang. Therefore, claim 25 is obvious over Thor et al. in view of Surasarang et al. and rejected.
Response to Arguments
Applicant's arguments filed 2/9/2026 have been fully considered but they are not persuasive.
Applicant asserts that “Rovero does not teach or suggest an absent residue adjacent to the Aspartic Acid residue for a gamma-constrained peptide.” (Applicant Reply, page 10, para. 1).
Rovero provides motivation to use the sequences of NKA(4-10): “However, while the activities of these compounds in the NK-1 (D.C.A.) and NK-3 (R.P.V.) systems decrease in parallel with the shortening of the peptide chain, a different pattern is observed in the NK-2 system where the most active compound is NKA (4-lo), twice as potent as NKA. These findings point to the fundamental role of Asp4 in the activation of NK-2 receptors.” This is sufficient motivation to not stop at Thr3 due to the increased activity in the NK-2 system.
Regarding the argument that Rovero actually teaches [β-Ala8]-NKA (4-10), this does not constitute a teaching away. MPEP 2145(X)(D)(1) states: “A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 553, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994).”
Applicant has not claimed an activity level that would require the [β-Ala8]-NKA (4-10), and therefore MPEP 2145(X)(D)(1) applies: “Furthermore, "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 692, 2023 USPQ2d 448 (Fed. Cir. 2023) ("a reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed.")”.
Regarding the issue of Lys 3 or Thr 3, it is not clear what difference this makes when the embodiment in question has no residue at all in this position. Rovero states that the critical residue is Asp 4: “These findings point to the fundamental role of Asp4 in the activation of NK-2 receptors.” (Rovero et al., page 266, col.2, para. 4). It is not impermissible hindsight to remove a residue at a position that Rovero has already removed a residue from. Applicant’s specification is no way need to teach this modification.
Regarding the teachings of Hagan, Thor already shows that Lys 3 is a workable residue in that position and Rovero shows that constructs truncated down to Asp 4 have superior activity against NK-2. It is not clear how the disclosure of another construct with Thr 3 is relevant to this analysis.
Hypothetically, if Applicant had showed and claimed a molecule with Asp 4 removed, this would almost certainly be non-obvious due to the enormous weight of evidence showing that Asp 4 is critical. However, as it stands, removing either Lys 3 or Thr 3 is obvious due to the increased NK-2 activity described by Rovero.
Applicant asserts: “One of ordinary skill in the art would not modify SEO ID No. 5 of Thor to replacement the Gly8 and Leu9 with a residue including a R-y-lactam based on Deal.” (Applicant’s Reply, page 13, para. 2).
Applicant cites Hagan, Rovero, and Saviano to show that Gly 8 increases NK-1 and NK-3 activity. However, Deal was cited with respect to NK-2 activity: “With particular relevance to this work, it has been reported that replacement of the Gly9 residue in SP-related peptides by Pro enhances NK-1 receptor selectivity,5 whereas introduction of D-Pro or an R-γ-lactam constraint at this position enhances NK-2 receptor selectivity.6” (Deal et al., page 4195, col. 1, para. 1).
MPEP 2145(X)(D)(1) applies in this scenario as well: “Furthermore, "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 692, 2023 USPQ2d 448 (Fed. Cir. 2023) ("a reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed.")”.
If Applicant were claiming a specific NK-1 or NK-3 activity, this assertion would hold more weight. However, this assertion does not directly address the motivation to introduce the lactam constraint of Deal into the sequence of Thor to improve NK-2 specificity. This is a legitimate motivation to combine and the existence of structure-activity combinations does not teach away from this combination.
Applicant asserts: “Rovero teaches away from substitution of the C-terminal Met residue with Nle” (Applicant Reply, page 14, para. 3).
Regarding the concern about the substitution being well-tolerated, MPEP 2143.02 states that: “Obviousness does not require absolute predictability, but at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976).”
Here, however, Rovero discloses that Nle is tolerated at that position albeit with a reduction in activity. However, recall that MPEP 2145(X)(D)(1) states: “A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 553, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994).”
The substitution of Nle is not being randomly selected, nor selected from Applicant’s specification. Rovero explicitly discloses that Nle is functional in this position. Because of the data disclosed by Rovero, this falls under simple substitution of one known element for another to obtain predictable results. The predictable results do not have to be absolutely predictable as described above.
If the present Application had substituted, for example, diphenylalanine or vinylglycine in 10 position, Rovero would likely not disclose a sufficiently predictable result for these amino acids, which would far more strongly favor non-obviousness.
Regarding the Arg 5 variant of claim 6, Thor SEQ ID NO: 1 and the resulting efficacy tests of said sequence show that Lys 5 show that this residue substitution is at a minimum tolerated and perhaps advantageous (Thor et al., col. 37, line 41). The disclosure of Thor is focused on agonizing the NK-2 receptor and system (Thor et al, col. 4, line 13) and therefore the lactam constraint described by Deal is a case of combining a modification known to increase NK-2 specificity with a molecule used to target NK-2. From there, it is an obvious modification to try Arg in place of Lys because of the known tolerance to substation disclosed by Trivedi.
If the present Application had substituted for example, a negatively charged amino acid in this position, peptide charge would not be preserved and Trivedi would likely not render this substitution obvious.
Regarding double patenting, Applicant arguments are unpersuasive as described above and therefore the non-statutory double patenting rejection is maintained below.
Maintained Rejections – Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1, 2, 4, 11, 16, 17, 22-24, and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 16, 25 of U.S. Patent No. 10,086,034 in view of Deal et al. (Deal, et al. Journal of medicinal chemistry 35.22: 4195-4204 (1992)).
Regarding claim 1, claim 1 recites
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Thor claim 25 discloses SEQ ID NO: 5, Asp Ser Phe Val Gly Leu Met-NH2. SEQ ID NO: 5 of Thor corresponds to SEQ ID NO: 11 of the present application in the case where Xaa1 is absent, Xaa3 is Ser, and B is Met-NH2. Thor does not disclose a gamma constraint between Gly and Leu.
However, Deal discloses that: “With particular relevance to this work, it has been reported that replacement of the Gly9 residue in SP-related peptides by Pro enhances NK-1 receptor selectivity,5 whereas introduction of D-Pro or an R-γ-lactam constraint at this position enhances NK-2 receptor selectivity.6” (Deal et al., page 4195, col. 1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add a gamma lactam constraint as suggested by Deal to SEQ ID NO: 5 of Thor to arrive at the claimed invention.
A person of ordinary skill in the art would have a reasonable expectation of success of adding the gamma lactam to SEQ ID NO: 5 of Thor because Deal discloses that it enhances NK-2 receptor selectivity as described above. A person of ordinary skill in the art would seek to enhance NK-2 receptor selectivity in order to reduce unwanted side effects or enable the usage of a lower dose.
Consequently, claim 1 is obvious over Thor et al. in view of Deal et al. and rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 recites the peptide compound of claim 1, wherein Xaa1 is absent, Xaa3 is Ser, and B is Met-NH2, or a pharmaceutically acceptable salt thereof (Compound A; SEQ ID NO: 1).
Thor claim 25 discloses SEQ ID NO: 5, Asp Ser Phe Val Gly Leu Met-NH2. SEQ ID NO: 5 of Thor corresponds to SEQ ID NO: 11 of the present application in the case where Xaa1 is absent, Xaa3 is Ser, and B is Met-NH2. Thor does not disclose a gamma constraint between Gly and Leu.
However, Deal discloses that: “With particular relevance to this work, it has been reported that replacement of the Gly9 residue in SP-related peptides by Pro enhances NK-1 receptor selectivity,5 whereas introduction of D-Pro or an R-γ-lactam constraint at this position enhances NK-2 receptor selectivity.6” (Deal et al., page 4195, col. 1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add a gamma lactam constraint as suggested by Deal to SEQ ID NO: 5 of Thor to arrive at the claimed invention.
A person of ordinary skill in the art would have a reasonable expectation of success of adding the gamma lactam to SEQ ID NO: 5 of Thor because Deal discloses that it enhances NK-2 receptor selectivity as described above. A person of ordinary skill in the art would seek to enhance NK-2 receptor selectivity in order to reduce unwanted side effects or enable the usage of a lower dose.
Consequently, claim 2 is obvious over Thor et al. in view of Deal et al. and rejected.
Regarding claim 4, claim 1 is obvious as described above. Claim 4 further recites the peptide compound of claim 1, wherein Xaa1 is absent, Xaa3 is Lys, and B is Met-NH2, or a pharmaceutically acceptable salt thereof (Compound C; SEQ ID NO: 3).
Thor discloses SEQ ID NO: 5, Asp4-Ser5-Phe6-Val7-Gly8-Leu9-Met10-NH2, which is same sequence claimed by Applicant claim 2 without the γ-lactam constraint at position 9 and with Ser in place of Lys.
Deal discloses that: “With particular relevance to this work, it has been reported that replacement of the Gly9 residue in SP-related peptides by Pro enhances NK-1 receptor selectivity,5 whereas introduction of D-Pro or an R-γ-lactam constraint at this position enhances NK-2 receptor selectivity.6” (Deal et al., page 4195, col. 1, para. 1).
Thor discloses SEQ ID NO: 1, which has the sequence: Asp Lys Phe Val Gly Leu Nle.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add a gamma lactam constraint as suggested by Deal to SEQ ID NO: 5 of Thor and make the Ser to Lys substitution as disclosed by Thor SEQ ID NO: 1.
A person of ordinary skill in the art would have a reasonable expectation of success of adding the gamma lactam to SEQ ID NO: 5 of Thor because Deal discloses that it enhances NK-2 receptor selectivity as described above and Thor discloses a Ser5 to Lys5 substitution in same context for the same purpose. A person of ordinary skill in the art would seek to enhance NK-2 receptor selectivity in order to reduce unwanted side effects or enable the usage of a lower dose and modulate peptide activity to be closer to that if SEQ ID NO: 1 of Thor.
Consequently, claim 4 is obvious over Thor et al. in view of Deal et al. and rejected.
Regarding claim 11, claim 1 is obvious as described above. Thor et al. claim 1 discloses: “A method for inducing one or both of urinary voiding and defecation in a mammal, which comprises administering on an as-needed basis to the mammal a therapeutically effective amount of a neurokinin 2 receptor (NK2R) agonist also having selectivity over neurokinin 1 (NK1R) and neurokinin 3 (NK3R) receptors, wherein the NK2R agonist is a NKA analogue, or a pharmaceutically acceptable salt thereof formulated as an immediate release dosage form, wherein the administering is by a mode selected from the group consisting of transmucosal, intramuscular, and subcutaneous, wherein the NK2R agonist or the pharmaceutically acceptable salt thereof, has a rapid onset and a short duration of action, to induce the as-needed one or both of urinary voiding and defecation.” Consequently, the use claimed by claim 11 is disclosed by Thor and therefore claim 11 is obvious over Thor et al. in view of Deal et al. and rejected.
Regarding claim 16, claim 11 is obvious as described above. Claim 16 recites; “The pharmaceutical composition of claim 11, wherein the compound has a selectivity for activation of human neurokinin 2 receptor (hNK2R) versus human neurokinin 1 receptor (hNK1R) of at least 20-fold, of at least 50-fold, of at least 100-fold, or of at least 200-fold.”
MPEP 2112.01(II) states: “"Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.” The structure of claim 16 is identical to that of claim 1. Therefore, the recited properties are necessarily present and claim 16 is obvious and rejected.
Regarding claim 17, claim 11 is obvious as described above. Thor et al. claim 16 discloses:
“The method of claim 15, wherein the one of voiding and defecation dysfunction is a result of one of spinal cord injury, traumatic brain injury, multiple sclerosis, spina bifida, degenerative brain disease, Alzheimer's, Parkinson's, dementia, diabetes, advanced age, or postoperative status, and combinations thereof.: Consequently, claim 17 is obvious and rejected.
Regarding claim 22, claim 1 is obvious as described above. Claim 1 of Thor et al. discloses: “ A method for inducing one or both of urinary voiding and defecation in a mammal, which comprises administering on an as-needed basis to the mammal a therapeutically effective amount of a neurokinin 2 receptor (NK2R) agonist also having selectivity over neurokinin 1 (NK1R) and neurokinin 3 (NK3R) receptors, wherein the NK2R agonist is a NKA analogue, or a pharmaceutically acceptable salt thereof formulated as an immediate release dosage form, wherein the administering is by a mode selected from the group consisting of transmucosal, intramuscular, and subcutaneous, wherein the NK2R agonist or the pharmaceutically acceptable salt thereof, has a rapid onset and a short duration of action, to induce the as-needed one or both of urinary voiding and defecation.”
Consequently, claim 22 is obvious over Thor et al. in view of Deal et al. and rejected.
Regarding claim 23, claim 22 is obvious as described above. Claim 1 of Thor et al. discloses: “ A method for inducing one or both of urinary voiding and defecation in a mammal, which comprises administering on an as-needed basis to the mammal a therapeutically effective amount of a neurokinin 2 receptor (NK2R) agonist also having selectivity over neurokinin 1 (NK1R) and neurokinin 3 (NK3R) receptors, wherein the NK2R agonist is a NKA analogue, or a pharmaceutically acceptable salt thereof formulated as an immediate release dosage form, wherein the administering is by a mode selected from the group consisting of transmucosal, intramuscular, and subcutaneous, wherein the NK2R agonist or the pharmaceutically acceptable salt thereof, has a rapid onset and a short duration of action, to induce the as-needed one or both of urinary voiding and defecation.”
Consequently, claim 22 is obvious over Thor et al. in view of Deal et al. and rejected.
Regarding claim 28, claim 22 is obvious as described above. Claim 3 of Thor discloses: “The method of claim 1, wherein the transmucosal administering comprises transbuccal, lingual, sublingual, inhalation, intranasal, topical, transrectal, or transurethral.” Consequently, claim 28 is obvious over Thor et al. in view of Deal et al. and rejected.
Claims 3 and 5 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 16, 25 of U.S. Patent No. 10,086,034 in view of Deal et al. (Deal, et al. Journal of medicinal chemistry 35.22: 4195-4204 (1992)) as applied to claim 1 above, further in view of Rovero et al. (Rovero, et al. Neuropeptides 13.4: 263-270 (1989).
Regarding claim 3, claim 1 is obvious as described above. Claim 3 further recites the peptide compound of claim 1, wherein Xaa1 is absent, Xaa3 is Ser, and B is Nle-NH2, or a pharmaceutically acceptable salt thereof (Compound B; SEQ ID NO: 2).
Thor discloses SEQ ID NO: 5, Asp4-Ser5-Phe6-Val7-Gly8-Leu9-Met10-NH2, which is same sequence claimed by Applicant claim 2 without the γ-lactam constraint at position 9.
Deal discloses that: “With particular relevance to this work, it has been reported that replacement of the Gly9 residue in SP-related peptides by Pro enhances NK-1 receptor selectivity,5 whereas introduction of D-Pro or an R-γ-lactam constraint at this position enhances NK-2 receptor selectivity.6” (Deal et al., page 4195, col. 1, para. 1).
Rovero discloses the Nle substitution: “This study showed that the replacement of Met by the isosteric group Nle is quite well tolerated by the NK-2 receptor and therefore [Nle10]-NKA showed some selectivity. When made in the NKA (4-10), the same substitution brought to the of a fairly selective agonist for the NK-2 receptor, namely [Nle10]-NKA (4-10).” (Rovero et al., page 268, col. 1, para.1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add a gamma lactam constraint as suggested by Deal to SEQ ID NO: 5 of Thor and make the Met to Nle substitution as described by Rovero to arrive at the claimed invention.
A person of ordinary skill in the art would have a reasonable expectation of success of adding the gamma lactam to SEQ ID NO: 5 of Thor because Deal discloses that it enhances NK-2 receptor selectivity as described above and Rovero discloses that a Met to Nle substitution successfully modulates selectivity of the peptide. A person of ordinary skill in the art would seek to enhance NK-2 receptor selectivity in order to reduce unwanted side effects or enable the usage of a lower dose.
Consequently, claim 3 is obvious over Thor et al. in view of Deal et al. as applied to claim 1, and further in view of Rovero et al. and rejected.
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the peptide compound of claim 1, wherein Xaa1 is absent, Xaa3 is Lys, and B is Nle-NH2, or a pharmaceutically acceptable salt thereof (Compound B; SEQ ID NO: 2).
Thor discloses SEQ ID NO: 5, Asp4-Ser5-Phe6-Val7-Gly8-Leu9-Met10-NH2, which is same sequence claimed by Applicant claim 2 without the γ-lactam constraint at position 9.
Deal discloses that: “With particular relevance to this work, it has been reported that replacement of the Gly9 residue in SP-related peptides by Pro enhances NK-1 receptor selectivity,5 whereas introduction of D-Pro or an R-γ-lactam constraint at this position enhances NK-2 receptor selectivity.6” (Deal et al., page 4195, col. 1, para. 1).
Rovero discloses the Nle substitution: “This study showed that the replacement of Met by the isosteric group Nle is quite well tolerated by the NK-2 receptor and therefore [Nle10]-NKA showed some selectivity. When made in the NKA (4-10), the same substitution brought to the of a fairly selective agonist for the NK-2 receptor, namely [Nle10]-NKA (4-10).” (Rovero et al., page 268, col. 1, para.1).
Thor discloses SEQ ID NO: 1, which has the sequence: Asp Lys Phe Val Gly Leu Nle.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add a gamma lactam constraint as suggested by Deal to SEQ ID NO: 5 of Thor and make the Met to Nle substitution as described by Rovero and the Ser to Lys substitution as described by Thor to arrive at the claimed invention.
A person of ordinary skill in the art would have a reasonable expectation of success of adding the gamma lactam to SEQ ID NO: 5 of Thor because Deal discloses that it enhances NK-2 receptor selectivity as described above and Rovero discloses that a Met to Nle substitution successfully modulates selectivity of the peptide. Thor also shows that Ser to Lys results in an efficacious peptide with SEQ ID NO: 1. A person of ordinary skill in the art would seek to enhance or modulate NK-2 receptor selectivity in order to reduce unwanted side effects or enable the usage of a lower dose.
Consequently, claim 5 is obvious over Thor et al. in view of Deal et al. as applied to claim 1 above, further in view of Rovero et al. rejected.
Claim 6 is rejected on the ground of nonstatutory double patenting \s being unpatentable over claims 1, 3, 16, 25 of U.S. Patent No. 10,086,034 in view of Deal et al. (Deal, et al. Journal of medicinal chemistry 35.22: 4195-4204 (1992)) as applied to claim 1 above, further in view of Trivedi et al. (Trivedi, et al. Protein Science 29.11 : 2150-2163 2020))..
Regarding claim 6, claim 1 is obvious as described above. Claim 6 further recites the peptide compound of claim 1, wherein Xaa1 is absent, Xaa3 is Arg, and B is Met-NH2, or a pharmaceutically acceptable salt thereof (Compound E; SEQ ID NO: 5).
Thor discloses SEQ ID NO: 5, Asp4-Ser5-Phe6-Val7-Gly8-Leu9-Met10-NH2, which is same sequence claimed by Applicant claim 2 without the γ-lactam constraint at position 9 and with Ser in place of Lys.
Deal discloses that: “With particular relevance to this work, it has been reported that replacement of the Gly9 residue in SP-related peptides by Pro enhances NK-1 receptor selectivity,5 whereas introduction of D-Pro or an R-γ-lactam constraint at this position enhances NK-2 receptor selectivity.6” (Deal et al., page 4195, col. 1, para. 1).
Thor discloses SEQ ID NO: 1, which has the sequence: Asp Lys Phe Val Gly Leu Nle.
Furthermore, Trivedi discloses that according to both BLOSUM62 and GPCRtm substitution matrices, a lysine to arginine substitution is well-tolerated (Trivedi et al., page 2157, Table 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add a gamma lactam constraint as suggested by Deal to SEQ ID NO: 5 of Thor and make the Ser to Lys substitution as disclosed by Thor.
A person of ordinary skill in the art would have a reasonable expectation of success of adding the gamma lactam to SEQ ID NO: 5 of Thor because Deal discloses that it enhances NK-2 receptor selectivity as described above and Thor discloses a Ser5 to Lys5 substitution in same context for the same purpose. Also, Trivedi shows that a lysine to arginine substitution has a reasonable expectation of success based on the matrix substitution scores.
A person of ordinary skill in the art would seek to enhance NK-2 receptor selectivity in order to reduce unwanted side effects or enable the usage of a lower dose and modulate peptide activity to be closer to that if SEQ ID NO: 1 of Thor. A person of ordinary skill in the art would find it obvious to try a lysine to arginine substitution based off the Trivedi matrix in order to see if the properties can be further improved.
Consequently, claim 6 is obvious over Thor et al. in view of Deal et al. as applied to claim 1 above, further in view of Trivedi et al. and rejected.
Claims 7 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 16, 25 of U.S. Patent No. 10,086,034 in view of Deal et al. (Deal, et al. Journal of medicinal chemistry 35.22: 4195-4204 (1992)) as applied to claim 1 above, and further in view of Rovero et al. (Rovero, et al. Neuropeptides 13.4: 263-270 (1989) and Trivedi et al. (Trivedi, et al. Protein Science 29.11 : 2150-2163 2020)).
Regarding claim 7, claim 1 is obvious as described above. Claim 7 further recites the peptide compound of claim 1, wherein Xaa1 is absent, Xaa3 is Arg, and B is Nle-NH2, or a pharmaceutically acceptable salt thereof (Compound F; SEQ ID NO: 6).
Thor discloses SEQ ID NO: 5, Asp4-Ser5-Phe6-Val7-Gly8-Leu9-Met10-NH2, which is same sequence claimed by Applicant claim 2 without the γ-lactam constraint at position 9.
Deal discloses that: “With particular relevance to this work, it has been reported that replacement of the Gly9 residue in SP-related peptides by Pro enhances NK-1 receptor selectivity,5 whereas introduction of D-Pro or an R-γ-lactam constraint at this position enhances NK-2 receptor selectivity.6” (Deal et al., page 4195, col. 1, para. 1).
Rovero discloses the Nle substitution: “This study showed that the replacement of Met by the isosteric group Nle is quite well tolerated by the NK-2 receptor and therefore [Nle10]-NKA showed some selectivity. When made in the NKA (4-10), the same substitution brought to the of a fairly selective agonist for the NK-2 receptor, namely [Nle10]-NKA (4-10).” (Rovero et al., page 268, col. 1, para.1).
Thor discloses SEQ ID NO: 1, which has the sequence: Asp Lys Phe Val Gly Leu Nle.
Furthermore, Trivedi discloses that according to both BLOSUM62 and GPCRtm substitution matrices, a lysine to arginine substitution is well-tolerated (Trivedi et al., page 2157, Table 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add a gamma lactam constraint as suggested by Deal to SEQ ID NO: 5 of Thor and make the Met to Nle substitution as described by Rovero and the Ser to Lys substitution as described by Thor to arrive at the claimed invention.
A person of ordinary skill in the art would have a reasonable expectation of success of adding the gamma lactam to SEQ ID NO: 5 of Thor because Deal discloses that it enhances NK-2 receptor selectivity as described above and Thor discloses a Ser5 to Lys5 substitution in same context for the same purpose. Also, Trivedi shows that a lysine to arginine substitution has a reasonable expectation of success based on the matrix substitution scores.
A person of ordinary skill in the art would seek to enhance NK-2 receptor selectivity in order to reduce unwanted side effects or enable the usage of a lower dose and modulate peptide activity to be closer to that if SEQ ID NO: 1 of Thor. A person of ordinary skill in the art would find it obvious to try a lysine to arginine substitution based off the Trivedi matrix in order to see if the properties can be further improved.
Consequently, claim 7 is obvious over Thor et al. in view of Deal et al as applied to claim 1 above, and further in view of Rovero et al. and Trivedi et al. and rejected.
Claims 18 and 24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 16, 25 of U.S. Patent No. 10,086,034 in view of Deal et al. (Deal, et al. Journal of medicinal chemistry 35.22: 4195-4204 (1992)) and Rovero et al. (Rovero, et al. Neuropeptides 13.4: 263-270 (1989), further in view of Muheem et al. (Muheem, et al. Saudi Pharmaceutical Journal 24.4: 413-428 (2016)).
Regarding claim 18, claim 11 is obvious as described above. Compound C is obvious as described above.
Claim 18 further recites: “… the composition is formulated for compatibility with a hydrophilic peptide compound in an aqueous solution.”
Muheem discloses that “The two important approaches for formulation of protein and peptides by oral route include: use of absorption enhancers and enzymatic inhibitor. Being charged, large in size and hydrophilic, proteins and peptides are notoriously poor permeators (and thus exhibit poor oral bioavailability per se).” (Muheem et al., page 417, col. 2, para. 3). Consequently, it would been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine Compound C of Thor, Deal and Rovero and utilize the formulation strategies of Muheem to address the issues of permeation and bioavailability to arrive at the claimed invention. A person of ordinary skill in the art would be motivated to do this in order to address the shortcomings disclosed by Muheem. Therefore, claim 18 is obvious over Thor et al. in view of Rovero et al., Deal et al., and further in view of Muheem et al. and rejected.
Regarding claim 24, claim 4 is obvious as described above. Furthermore, claim 18 is obvious as described above.
Thor et al. claim 1 discloses: “ A method for inducing one or both of urinary voiding and defecation in a mammal, which comprises administering on an as-needed basis to the mammal a therapeutically effective amount of a neurokinin 2 receptor (NK2R) agonist also having selectivity over neurokinin 1 (NK1R) and neurokinin 3 (NK3R) receptors, wherein the NK2R agonist is a NKA analogue, or a pharmaceutically acceptable salt thereof formulated as an immediate release dosage form, wherein the administering is by a mode selected from the group consisting of transmucosal, intramuscular, and subcutaneous, wherein the NK2R agonist or the pharmaceutically acceptable salt thereof, has a rapid onset and a short duration of action, to induce the as-needed one or both of urinary voiding and defecation.”
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the composition of claims 4 and 18 to execute the method disclosed by Thor. A person of ordinary skill in the art would be motivated to use these compositions in an aqueous system to overcome the issues disclosed by Muheem above. A person of ordinary skill in the art would have a reasonable expectation of success because Thor is written to NK2R agonists. Consequently, claim 24 is obvious over unpatentable over Thor et al. in view of Deal et al. and Rovero et al., further in view of Muheem et al..
Claim 19 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 16, 25 of U.S. Patent No. 10,086,034 in view of Deal et al. (Deal, et al. Journal of medicinal chemistry 35.22: 4195-4204 (1992)) and Rovero et al. (Rovero, et al. Neuropeptides 13.4: 263-270 (1989), further in view of Surasarang et al. (Surasarang, et al. Drug development and industrial pharmacy 44.2: 184-198 (2018)).
Regarding claim 19, claim 11 is obvious as described above. Compound C is obvious as described above. Claim 19 further recites: “… wherein the composition comprises the peptide compound C, D, E, F, or G formulated for administering in an aqueous isotonic solution.”
Surasarang discloses that “It is important to obtain isotonic solution after reconstitution of the lyophilized formulations. The non-isotonic solutions can cause the release of histamine, which resulted from changing of the osmotic load around mast cells [47]. The release of histamine is responsible for bronchoconstriction .” (Surasarang et al., page 188, col. 1, para. 3). Consequently, it would been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine Compound C of Thor, Deal, and Rovero and utilize the formulation strategies of Surasarang to address the issues of undesirable release of histimine. A person of ordinary skill in the art would be motivated to do this in order to address the issue of release of histimine as disclosed by Surasarang. Therefore, claim 19 is obvious over Thor et al. in view of Rovero et al., and Deal et al., further in view of Surasarang et al. and rejected.
Claim 20 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 16, 25 of U.S. Patent No. 10,086,034 in view of Deal et al. (Deal, et al. Journal of medicinal chemistry 35.22: 4195-4204 (1992)), further in view of Akanbi, et al. (Akanbi, et al. Colloids and surfaces B: Biointerfaces 75.2: 526-531 (2010)).
Regarding claim 20, claim 11 is obvious as described above. Compound A is obvious as described above. Claim 19 further recites: “…wherein the composition comprises the peptide compound A or B and the composition is formulated for compatibility with a hydrophobic peptide compound.”.
Akanbi discloses that: “The poor water solubility of many drugs requires a specific formulation to achieve a sufficient bioavailability after oral administration. Suspensions of small drug particles can be used to improve the bioavailability. We here show that the fungal hydrophobin SC3 can be used to make suspensions of water insoluble drugs.” (Akanbi, et al., page 526, Abstract).
Consequently, it would been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine Compound A of Thor and Rovero and utilize the formulation strategies of Akanbi to address the issues of delivery of hydrophobic peptides. A person of ordinary skill in the art would be motivated to do this in order to address the issue of delivery of hydrophobic peptides as disclosed by Surasarang. Therefore, claim 20 is obvious over Thor et al. in view of Rovero et al., as evidenced by Deal et al., further in view of Akanbi et al. and rejected.
Claim 25 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 16, 25 of U.S. Patent No. 10,086,034 and Deal et al. (Deal, et al. Journal of medicinal chemistry 35.22: 4195-4204 (1992)) as applied to claim 1 above, further in view of Surasarang et al. (Surasarang, et al. Drug development and industrial pharmacy 44.2: 184-198 (2018)).
Regarding claim 25, claim 22 is obvious as described above.
Surasarang discloses that “It is important to obtain isotonic solution after reconstitution of the lyophilized formulations. The non-isotonic solutions can cause the release of histamine, which resulted from changing of the osmotic load around mast cells [47]. The release of histamine is responsible for bronchoconstriction .” (Surasarang et al., page 188, col. 1, para. 3).
Consequently, it would been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of Thor with the isotonic composition of Surasarang to address the issues of undesirable release of histamine. A person of ordinary skill in the art would be motivated to do this in order to address the issue of release of histamine as disclosed by Surasarang. Therefore, claim 25 is obvious over Thor et al. in view of Deal et al., further in view of Surasarang et al. and rejected.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/DAVID PAUL BOWLES/ Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654
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