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 .
Election/Restrictions
Applicant’s election without traverse of the species Compound ID 383 in the reply filed on February 16, 2026, is acknowledged.
Compound 383 (SEQ ID NO: 43) is free of the prior art. Compounds 305 (SEQ ID NO: 4), 344 (SEQ ID NO: 23), 369 (SEQ ID NO: 35), 395 (SEQ ID NO: 54), and 398 (SEQ ID NO: 58) are also free of the prior art.
The search was extended to Compound 304 (SEQ ID NO: 3) and prior art was found. Claims 1-2, 7, 9, 12-15, 18, 21, 23, 28, and 30-32 encompass Compound 304.
The search was not extended further in accordance with MPEP § 803.02.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Nucleotide and/or Amino Acid Sequence Disclosures
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). The amino acid sequences in claims 19 and 20 require sequence identifiers every time that they appear in the claims and specification.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Interpretation
Neurokinin receptor 2 (NK2R) is also known as NK-2 receptor, NK-2R, Neurokinin A receptor
Tachykinin receptor 2, substance K receptor, SKR, TACR2, NKNAR.
In claim 1, the phrase “(A) is a peptide comprising an amino acid sequence of the general formula X1X2X3X4X5X6X7” (emphasis added) is interpreted as peptides comprising the full-length X1X2X3X4X5X6X7 as well as fragments thereof. If Applicant wants to limit the claim to peptides comprising the full-length X1X2X3X4X5X6X7, the indefinite article “an” should be replaced with the definite article “the”.
As stated in the specification at page 8, lines 14-15, capital letter abbreviations of 1- and 3-letter code amino acids indicate L-amino acids, whereas lower case letter abbreviations indicate D-amino acids. Therefore, D, E, K, R, H, Y, F, m-Y, V, W, M, L, I, A, V, T, S, N, Q, Aib, bA, Me-Leu, Nle, Mox, and 4MeOF in the claims are limited to L-amino acids.
The amino acid Mox is defined on page 8 of the specification.
There is no limiting definition of “terminal amino acid” in the specification. BRI of “and wherein (B) is covalently linked to a terminal amino acid” in claim 1 includes the first amino acid at the N-terminus, the last amino acid at the C-terminus as well as amino acids near these positions. Therefore, a modification at X2 is included in the scope of the claim.
Claim 21 recites SEQ ID NO: 1 to SEQ ID NO: 57. The sequence listing entries denote modifications at various positions Conj-Neu-C18, Conj-Neu, Conj-Pos1, and Conj-Pos2. These structures are defined in Example 6 of the specification. The sequence listing entries also denote modifications at various positions Conj-Neu-C14, Conj-Neu-C16, and Conj-Neu-C20, which are interpreted as 2xOEG-gamma-Glu-C14 diacid, 2xOEG-gamma-Glu-C16 diacid, and 2xOEG-gamma-Glu-C20 diacid in Example 6 of the specification, respectively.
Claim Objections
Claim 22 is objected to because of the following informalities: the use of semicolons to separate adjacent amino acid residues in the depiction of several compounds is unconventional (ID 369, SEQ ID NO: 35; ID 395, SEQ ID NO: 54; ID 398, SEQ ID NO: 58). Because the compounds appear in the original sequence listing and because their synthesis is described in the original specification, there is not an indefiniteness issue; the semicolons are used to indicate a peptide bond. However, Applicant is encouraged to amend the structures to use a dash, chemical structures, or adjacent single letter codes to improve readability for the public. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 5, 7-9, 12-15, 18, 23, 28, and 30-32 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
The claims are drawn to agonists of neurokinin receptor 2 (NK2R) of formula (I). Formula (I) has two components: A) a peptide, and B) a conjugated moiety.
The peptide component (A) is an analog of residues 4-10 of neurokinin A, the ligand for NK2R, comprising X1X2X3X4X5X6X7 as well as fragments thereof wherein X1 is D or E; X2 is K, R, or H; X3 is Y, F, meta-tyrosine (m-Y), V, W, M, L, I, or A; X4 is V, T, S, N, Q, G, or A; X5 is G, Aib, S, V, L, b-alanine, or I; X6 is L, I, A, or N-methyl leucine (Me-Leu); and X7 is norleucine (Nle), methoxinine (Mox), M, 4-fluorophenylalanine (4fF) or 4-methoxyphenylalanine (4MeOF). Each variable in X1X2X3X4X5X6X7 includes the native amino acid from neurokinin A as an option except for X2. In native neurokinin A X2, which corresponds to position 5, is serine whereas in the claimed formula this position is a positively charged residue K, R, or H.
The conjugated component (B) (aka protractor) is linked to a terminal amino acid of (A) and is of general formula (II) Fa-Lg, wherein: Fa is lipid moiety containing 15-18 CH2 groups flanked by two carbonyls, wherein the terminal end of the moiety may be -OH, -OC1-6, NH2, -NHC1-6, or -N(C1-6)2; and Lg is a linker having the structure of an amine and carbonyl separated by a chain of 18 to 23 backbone atoms selected from C, O, and N.
Only those compounds meeting the structural and functional requirements of the genus are encompassed by the claim. Therefore, the claim encompasses all of the compounds meeting the structural requirements of formula (I) that are also able to agonize NK2R. Although with the aid of a computer it may be possible to determine the amino acid sequences of the peptides and the structure of protractors that meet the structural requirements of the claim, it is not readily apparent from the claims or the specification which of these compounds are also able to activate the neurokinin receptor 2.
Several embodiments of the invention were reduced to practice including compound ID 304, and the compounds in claim 22 compound IDs 305, 344, 369, 383, 395, and 398.1 As discussed above the claim scope is potentially enormous depending on how many of the compounds that meet the structural requirements are also able to function as NK2R agonists; in comparison, the scope of the description which only includes a small number of species, is extremely narrow. The actual reduction to practice is limited to species wherein A consists of a heptapeptide X1X2X3X4X5X6X7 wherein X1 is D or E; X2 is K or R (excluding H); X3 is Y, F, or m-Y (excluding V, W, M, L, I, and A); X4 is V or T (excluding S, N, Q, G, and A); X5 is G or Aib (excluding S, V, L, b-alanine, and I); X6 is L or M-Leu (excluding I and A); and X7 is Nle, Mox, or 4fF (excluding M and 4MeOF). Peptides of other lengths and peptides of any length containing the excluded amino acids were not reduced to practice. In addition, the actual reduction to practice is limited to compounds with conjugated moiety Conj-Neu-C18DA, excluding non-fatty diacid moieties and other linkers. Therefore, one of ordinary skill in the art would not consider the actual reduction to practice to be representative of the full scope of the claimed genus.
The data presented in the specification do not suggest the physical basis for the NK2R agonist activity and therefore do not describe which structural changes could be made while preserving function. The specification does not describe which residues form the NK2R binding site, influence the binding site formation indirectly, or have a role in the overall stability and dynamics of the peptide. The Understanding the physical basis for NK2R agonist activity is critical to determining which of the sequences that meet the structural requirements of the genus also meet the functional requirements of the genus.
The structure and function analysis of the claimed genus reported in the specification is limited to an evaluation of peptides wherein X1 is D or E; X2 is K or R (excluding H); X3 is Y, F, or m-Y (excluding V, W, M, L, I, and A); X4 is V, T, or S (excluding N, Q, G, and A); X5 is G, Aib, or b-ala (excluding S, V, L, and I); X6 is L or M-Leu (excluding I and A); and X7 is M, Nle, Mox, or 4fF (excluding 4MeOF). In addition, there is no analysis of structure and function for compounds with the conjugated moiety attached to the C-terminus of the peptide. Example 7 illustrates that activity and selectivity are sensitive to even small changes in the peptide structure.
In addition, the prior art is unpredictable with respect to the use of NK2R agonists to treat disease. Other than the prior art of Gerhart-Hines et al. (WO 2021/073742 A1), which shares a common inventor with the instant application and which was not published prior to the instant application and qualifies as prior art based only upon the earlier effectively filed date of the reference, the prior art fails to disclose the use of NK2R agonists for the treatment of obesity, diabetes, and insulin resistance. Therefore, there is nothing in the prior art that can be used to predict compounds of formula (I) useful for treating obesity, diabetes, and insulin resistance. The prior art does acknowledge the use of NK2R agonists for treating voiding dysfunction (e.g. Thor et al. US 2016/0175382 A1). However, the NK2R agonists reported by Thor et al. and others are designed to have a rapid onset and short duration of action. The compounds induce urinary voiding and defecation on-demand. The short duration of action permits the activated muscles to relax, allowing storage of newly-formed urine and stool, and thereby preventing subsequent incontinence. The short duration of action also minimizes side-effects in other organs systems and enables administration multiple times per day to initiate voiding. Thor et al. paragraph [0055]. Therefore, there is nothing in the prior art that can be used to predict whether compounds of formula (I), which comprise a lipid protractor moiety that binds HSA and prolongs serum half-life of the agonist, are useful for treating dysfunctional voiding.
For all of the reasons presented above, one of ordinary skill in the art would not know which of the countless compounds that meet the structural requirements of the claims would also be able to function as NK2R agonists. The specification does not make clear which compounds are in the genus and which are not because it does not describe the physical basis for the claimed activity, NK2R agonism. In other words, the specification does not describe which compounds to make.
For these reasons, the skilled artisan would not reasonably conclude that the inventor(s), at the time the application was filed, had possession of the full scope of the claimed invention.
Claims 1-2, 5, 7-9, 12-15, 18, 21, 23, 28, 30-32, and 37-39 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for using the compounds of claim 22 in in vitro assays for NK2K agonism, compound ID 304, 305, 344, and 383 to treat obesity, and compound ID 344 to treat insulin resistance, diabetes, and dysfunctional voiding, does not reasonably provide enablement for the use of the full scope of formula (I) to treat all NK2R mediated disorders. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
To comply with the enablement requirements of 35 U.S.C. §112, first paragraph, a specification must adequately teach how to make and how to use a claimed invention throughout its scope, without undue experimentation. Plant Genetic Systems N.V. v. DeKalb Genetics Corp., 315 F.3d 1335, 1339, 65 USPQ2d 1452, 1455 (Fed. Cir. 2003). There are a variety of factors which may be considered in determining whether a disclosure would require undue experimentation. These factors include: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The Nature of the Invention
The invention is compounds and their use in the treatment of disorders mediated by the neurokinin receptor 2 (NK2R).
The breadth of the claims
The claims are drawn to agonists of NK2R of formula (I). Formula (I) has two components: A) a peptide, and B) a conjugated moiety.
The peptide component (A) is an analog of residues 4-10 of neurokinin A, the ligand for NK2R, comprising X1X2X3X4X5X6X7 as well as fragments thereof wherein X1 is D or E; X2 is K, R, or H; X3 is Y, F, meta-tyrosine (m-Y), V, W, M, L, I, or A; X4 is V, T, S, N, Q, G, or A; X5 is G, Aib, S, V, L, b-alanine, or I; X6 is L, I, A, or N-methyl leucine (Me-Leu); and X7 is norleucine (Nle), methoxinine (Mox), M, 4-fluorophenylalanine (4fF) or 4-methoxyphenylalanine (4MeOF). Each variable in X1X2X3X4X5X6X7 includes the native amino acid from neurokinin A as an option except for X2. In native neurokinin A X2, which corresponds to position 5, is serine whereas in the claimed formula this position is a positively charged residue K, R, or H.
The conjugated component (B) (aka protractor) is linked to a terminal amino acid of (A) and is of general formula (II) Fa-Lg, wherein: Fa is lipid moiety containing 15-18 CH2 groups flanked by two carbonyls, wherein the terminal end of the moiety may be -OH, -OC1-6, NH2, -NHC1-6, or -N(C1-6)2; and Lg is a linker having the structure of an amine and carbonyl separated by a chain of 18 to 23 backbone atoms selected from C, O, and N.
The diseases encompassed by the claims include but are not limited to metabolic disorders such as obesity, diabetes, and insulin resistance, as well as dysfunction voiding.
The State of the Prior Art and Level of Unpredictability
Other than the prior art of Gerhart-Hines et al. (WO 2021/073742 A1), which shares a common inventor with the instant application and which was not published prior to the instant application and qualifies as prior art based only upon the earlier effectively filed date of the reference, the prior art fails to disclose the use of NK2R agonists for the treatment of obesity, diabetes, and insulin resistance. Therefore, there is nothing in the prior art that can be used to predict compounds of formula (I) useful for treating metabolic disorders such as obesity, diabetes, and insulin resistance. The prior art does acknowledge the use of NK2R agonists for treating voiding dysfunction (e.g. Thor et al. US 2016/0175382 A1). However, the NK2R agonists reported by Thor et al. and others are designed to have a rapid onset and short duration of action. The compounds induce urinary voiding and defecation on-demand. The short duration of action permits the activated muscles to relax, allowing storage of newly-formed urine and stool, and thereby preventing subsequent incontinence. The short duration of action also minimizes side-effects in other organs systems and enables administration multiple times per day to initiate voiding. Thor et al. paragraph [0055]. Therefore, there is nothing in the prior art that can be used to predict whether compounds of formula (I), which comprise a lipid protractor moiety that binds HSA and prolongs serum half-life of the agonist, are useful for treating dysfunctional voiding on-demand.
The Level of Guidance in the Specification
The data presented in the specification do not suggest the physical basis for the NK2R agonist activity and therefore do not describe which structural changes could be made while preserving function. The specification does not describe which residues form the NK2R binding site, influence the binding site formation indirectly, or have a role in the overall stability and dynamics of the peptide. The Understanding the physical basis for NK2R agonist activity is critical to determining which of the sequences that meet the structural requirements of the genus also meet the functional requirements of the genus.
The structure and function analysis of the claimed genus reported in the specification is limited to an evaluation of peptides wherein X1 is D or E; X2 is K or R (excluding H); X3 is Y, F, or m-Y (excluding V, W, M, L, I, and A); X4 is V, T, or S (excluding N, Q, G, and A); X5 is G, Aib, or b-ala (excluding S, V, L, and I); X6 is L or M-Leu (excluding I and A); and X7 is M, Nle, Mox, or 4fF (excluding 4MeOF). In addition, there is no analysis of structure and function for compounds with the conjugated moiety attached to the C-terminus of the peptide. Example 7 illustrates that activity and selectivity are sensitive to even small changes in the peptide structure.
The Presence or Absence of Working Examples
Several embodiments of the invention were reduced to practice including compound ID 304, and the compounds in claim 22 compound IDs 305, 344, 369, 383, 395, and 398.2 As discussed above the claim scope is potentially enormous depending on how many of the compounds that meet the structural requirements are also able to function as NK2R agonists; in comparison, the scope of the description which only includes a small number of species, is extremely narrow. The actual reduction to practice is limited to species wherein A consists of a heptapeptide X1X2X3X4X5X6X7 wherein X1 is D or E; X2 is K or R (excluding H); X3 is Y, F, or m-Y (excluding V, W, M, L, I, and A); X4 is V or T (excluding S, N, Q, G, and A); X5 is G or Aib (excluding S, V, L, b-alanine, and I); X6 is L or M-Leu (excluding I and A); and X7 is Nle, Mox, or 4fF (excluding M and 4MeOF). Peptides of other lengths and peptides of any length containing the excluded amino acids were not reduced to practice. In addition, the actual reduction to practice is limited to compounds with conjugated moiety Conj-Neu-C18DA, excluding non-fatty diacid moieties and other linkers. Therefore, one of ordinary skill in the art would not consider the actual reduction to practice to be representative of the full scope of the claimed genus with respect to the compounds and their use in in vitro assays for NK2R agonism.
Regarding the methods of treatment, only a limited reduction to practice is presented. Example 10 discloses the effect of compound IDs 304, 305, 344, and 383 in a mouse model for weight loss. The model measures energy expenditure and calculates weight loss efficacy based on half-life. It is not clear from the specification whether any of these compounds actually cause weight loss in the obese mice. Example 11 discloses the effect of compound ID 344 on glucose metabolism in obese mice and shows that the compound improved glucose and insulin tolerance, suggesting a potential ability to treat insulin resistance and diabetes but not actually demonstrating treatment. Example 12 discloses the effect of compound ID 344 on dysfunctional voiding in mice and suggests a potential to treat dysfunctional voiding. The effect of duration of action is not evaluated in this model.
The Quantity of Experimentation Necessary
Considering the factors above, the skilled artisan would be burdened with undue experimentation in determining if one of the claimed compounds would be effective at NK2R agonism and treating diseases mediated by NK2R. The skilled artisan would be burdened with testing a broad range of compounds in in vitro NK2R activity assays. The active agonists would then have to be subjected to animal models of various diseases mediated by NK2R. The experimentation required represents years of inventive effort. When the above factors are weighed, it is the examiner's position that one skilled in the art could not practice the invention without undue experimentation.
Therefore, in view of the Wands factors, the claims appear to require undue experimentation to use the full scope of the claimed invention.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 19-21 are 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.
Regarding claims 19-20, the parenthetical phrases (compound 305) and (compound 383) are indefinite. In the specification, compound 305 and compound 383 are defined as compounds of formula (I) comprising a fully defined (A) and (B) (see Example 13). As a result, it is not clear how these names can be used to define just (A) in these claims. In addition, formula (B1) is not defined in the claims. Therefore, the structure of these compounds is indefinite.
Regarding claim 21, SEQ ID NOs: 23, 32, 41-44, 50, 52-53, and 55 contain Metox (metoxinine) at the amino acid residue corresponding to X7. Neither the specification nor the art define the structure of Metox (metoxinine). Therefore, the structure of these compounds is indefinite.
Regarding claim 21, “wherein the peptide (A)…consists of the sequence of” is indefinite because each SEQ ID NO corresponds to compounds of formula (I) comprising a fully defined (A) and (B) (see Example 13 and the sequence listing). It is not clear how these SEQ ID NOs can be used to define just (A) in these claims or if the claim is attempting to limit the claims to the species in Example 13 and the sequence listing. Because there are multiple plausible claim constructions, the claim is indefinite.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 21 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
SEQ ID NO: 2 fails to meet the definition of formula (I) of claim 1 because it contains two (B) groups whereas formula (I) only contains one (B) group. In addition, the specification states that the two (B) groups cause loss of activity (Example 9). Therefore, SEQ ID NO: 2 fails to meet the functional requirement of claim 1, NK2R agonist.
SEQ ID NOs: 7-9 and 17 fail to meet the definition of (A) in formula (I) of claim 1 because the amino acid residue corresponding to X2 in these compounds is serine whereas the claim requires lysine, arginine, or histidine at this position.
SEQ ID NO: 10 fails to meet the definition of (A) in formula (I) of claim 1 because the amino acid residue corresponding to X7 in this compound is cHexAla, whereas the claim requires norleucine, methoxinine, methionine, 4-fluorophenylalanine, or 4-methoxyphenylalanine at this position.
SEQ ID NOs: 11-12 fail to meet the definition of (A) in formula (I) of claim 1 because the amino acid residue corresponding to X4 in these compounds is Arg, whereas the claim requires valine, threonine, serine, asparagine, glutamine, glycine, or alanine at this position. In addition, the specification states that the Arg at this position causes loss of receptor activation properties (Example 7). Therefore, SEQ ID NOs: 11-12 fail to meet the functional requirement of claim 1 NK2R agonist.
SEQ ID NO: 14 comprises Conj-Pos2 and SEQ ID NOs: 15 and 19 comprise Conj-Neg. Conj-Pos2 and Conj-Neg fail to meet the definition of (B) in formula (I) of claim 1 because they contain Z with 17 and 13 atoms in the backbone, respectively, whereas the claim requires Z as a chain of 18 to 23 atoms in the backbone.
SEQ ID NO: 18 fails to meet the definition of (A) in formula (I) of claim 1 because the amino acid residue corresponding to X3 in this compound is 4-I-Phe, whereas the claim requires tyrosine, phenylalanine, meta-tyrosine, valine, tryptophan, methionine, leucine, isoleucine, or alanine at this position. In addition, the specification states that the 4-I-Phe at this position causes loss of receptor activation properties (Example 7). Therefore, SEQ ID NO: 18 fails to meet the functional requirement of claim 1, NK2R agonist.
SEQ ID NOs: 23, 32, 41-44, 50, 52-53, and 55 fail to meet the definition of (A) in formula (I) of claim 1 because the amino acid residue corresponding to X7 in these compounds is Metox (metoxinine), whereas the claim requires norleucine, methoxinine, methionine, 4-fluorophenylalanine, or 4-methoxyphenylalanine at this position.
SEQ ID NOs: 24-25 fail to meet the definition of (A) in formula (I) of claim 1 because the amino acid residue corresponding to X4 in these compounds is Ile, whereas the claim requires valine, threonine, serine, asparagine, glutamine, glycine, or alanine at this position.
SEQ ID NO: 26 fails to meet the definition of (A) in formula (I) of claim 1 because the amino acid residue corresponding to X7 in this compound is Phe, whereas the claim requires norleucine, methoxinine, methionine, 4-fluorophenylalanine, or 4-methoxyphenylalanine at this position.
SEQ ID NO: 27 fails to meet the definition of (A) in formula (I) of claim 1 because the amino acid residue corresponding to X3 in this compound is dPhe, whereas the claim requires tyrosine, phenylalanine, meta-tyrosine, valine, tryptophan, methionine, leucine, isoleucine, or alanine each in L-form at this position. In addition, the specification states that the dPhe at this position causes loss of receptor activation properties (Example 7). Therefore, SEQ ID NO: 27 fails to meet the functional requirement of claim 1, NK2R agonist.
SEQ ID NO: 30 fails to meet the definition of (A) in formula (I) of claim 1 because the amino acid residue corresponding to X3 in this compound is Pro, whereas the claim requires tyrosine, phenylalanine, meta-tyrosine, valine, tryptophan, methionine, leucine, isoleucine, or alanine at this position. In addition, the specification states that the Pro at this position causes loss of receptor activation properties (Example 7). Therefore, SEQ ID NO: 30 fails to meet the functional requirement of claim 1, NK2R agonist.
SEQ ID NO: 31 fails to meet the definition of (A) in formula (I) of claim 1 because the amino acid residue corresponding to X4 in this compounds is Tyr, whereas the claim requires valine, threonine, serine, asparagine, glutamine, glycine, or alanine at this position.
SEQ ID NO: 33 and SEQ ID NO: 34 comprise Conj-Neu-C16 and Conj-Neu-C14, respectively. These modifications fail to meet the definition of (B) in formula (I) of claim 1 because they contain n is 11 and 13, respectively, whereas the claim requires n is 14 to 17.
SEQ ID NOs: 38 and 39 are not modified at all with a group that meets the definition of (B) in claim 1.
SEQ ID NOs: 45, 55, and 57 fail to meet the definition of (A) in formula (I) of claim 1 because the amino acid residue corresponding to X5 in these compounds is dSer, whereas the claim requires glycine or 2-aminoisobutyric acid, serine, alanine, valine, leucine, beta-alanine, or isoleucine each in L-form at this position.
Therefore, claim 21 fails to include all the limitations of the claim upon which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 7, 9, 12-15, 18, 21, 23, 28, and 30-32 are rejected under 35 U.S.C. 103 as being obvious over Gerhart-Hines et al. (WO 2021/073742 A1; FP6, IDS 8/2/2023) in view of Lau et al. (NPL 1, IDS 2/16/2026).
The applied reference WO 2021/073742 A1 has a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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.
Determining the scope and contents of the prior art.
Gerhart-Hines et al. teach Tac2 agonists for treating diabetes and/or obesity. The Tacr2 agonists activate brown and beige/brite adipose tissue independently of norepinephrine (NE)/b-adrenergic receptor signaling. The Tacr2 agonists cause an increase in oxygen consumption rate, glucose absorption, energy consumption and heat production in brown and beige adipocytes. The Tacr2 agonists activate brown adipose tissue without causing deleterious side effects such as elevated blood pressure and heart rate. Gerhart-Hines et al. page 2, lines 6-18.
Gerhart-Hines et al. teach that the Tac2 agonist may be a peptide consisting of Neurokinin A or a functional analogue or fragment thereof such as [Lys5, Me-Leu9, Nle10]NK4-(4-10) (SEQ ID NO: 9) Gerhart-Hines et al. page 15, lines 30-35. [Lys5, Me-Leu9, Nle10]NK4-(4-10) (SEQ ID NO: 9) corresponds to formula (A) of instant claim 1 wherein
X1 is aspartic acid (D);
X2 is lysine (K);
X3 is phenylalanine (F);
X4 is valine (V);
X5 is glycine (G);
X6 is methyl-leucine (Me-Leu); and
X7 is norleucine (Nle). It is identical to the peptide or (A) portion of instant Compound 304 (SEQ ID NO: 3).
Gerhart-Hines et al. teach that the Tac2 agonist may be a peptide covalently linked to a conjugated moiety to improve its physical properties, such as solubility, stability, or half-life. Gerhart-Hines et al. page 20, line 25 - page 24, line 20. Gerhart-Hines et al. teach that the conjugated moiety may be a fatty acid such as capric, lauric, myristic, palmitic, stearic, or arachidic acid. Gerhart-Hines et al. teach that the conjugated moiety may be attached to the terminal amino acid or to a lysine side chain fatty acid such as capric, lauric, myristic, palmitic, stearic, or arachidic acid. Gerhart-Hines et al. page 23, lines 5-33.
Gerhart-Hines et al. teach that the peptide may C-terminal amidated. Gerhart-Hines et al. page 22, lines 16-20.
Gerhart-Hines et al. teach pharmaceutical compositions comprising the Tac2 agonists and pharmaceutically acceptable carriers and excipients. Gerhart-Hines et al. page 24, line 22 - page 26, line 11.
Gerhart-Hines et al. teach methods of treating insulin resistance, diabetes, and/or obesity comprising administering the Tac2 agonists. Gerhart-Hines et al. page 26, line 13 - page 32, line 35.
Ascertaining the differences between the prior art and the claims at issue.
Gerhart-Hines et al. does not teach [Lys5, Me-Leu9, Nle10]NK4-(4-10) conjugated to (B) of formula (I) in instant claim 1.
Resolving the level of ordinary skill in the pertinent art.
Lau et al. teach fatty acid moieties and linking chemistry useful for conjugation to GLP-1 agonist peptides. The conjugated fatty acids increase albumin affinity and protect the peptide against metabolic degradation, thereby extending the half-life of the peptide agonist for once-weekly dosing in the treatment of diabetes and obesity. Lau et al. abstract. The conjugated group include species of instant variable (B) in formula (I) including the structure shown in instant claim 21 and present in species Compound 304 (SEQ ID NO: 3). Lau et al. Table 1 and Figure 1.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The specification does not provide a comparison between the closest prior art of [Lys5, Me-Leu9, Nle10]NK4-(4-10) (SEQ ID NO: 9) taught by Gerhart-Hines et al. and instant Compound 304 (SEQ ID NO: 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the C18 diacid protractor and gGlu-2xOEG linker taught by Lau et al. for the conjugated moiety in the Tac2 agonists taught by Gerhart-Hines et al. The rationale for obviousness is simple substitution of one known element for another to obtain predictable results (MPEP § 2143.01(B)). The relevant findings for this rationale are as follows.
(1) The prior art contained a product which differed from the claimed device by the substitution of some element with other elements. In the instant case, the primary reference teaches a Tac2 agonist [Lys5, Me-Leu9, Nle10]NK4-(4-10) (SEQ ID NO: 9) conjugated to a moiety which differs from the claimed species Compound 304 by the substitution of the C18 diacid protractor and gGlu-2xOEG for the conjugate moiety. Therefore, prior art contained a product which differed from the claimed device by the substitution of some element with other elements.
(2) The substituted components and their functions were known in the art. Lau et al. teach the structure shown in instant claim 21 and present in species Compound 304 (SEQ ID NO: 3), the C18 diacid protractor and gGlu-2xOEG. Lau et al. Table 1 and Figure 1. The function of the C18 diacid protractor and gGlu-2xOEG is known in the art because Lau et al. teach the structure increases albumin affinity and protects the peptide to which it is conjugated against metabolic degradation, thereby extending its half-life for once-weekly dosing in the treatment of diabetes and obesity. Lau et al. abstract. Therefore, the substituted components and their functions were known in the art.
(3) One of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable. One of ordinary skill in the art would expect that the C18 diacid protractor and gGlu-2xOEG performs the function of increasing albumin affinity and protection of the peptide to which it is conjugated against metabolic degradation in the combination because this is the function taught by Lau et al. (abstract). Therefore, one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable.
(4) Whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness. The specification does not provide a comparison between the closest prior art of [Lys5, Me-Leu9, Nle10]NK4-(4-10) (SEQ ID NO: 9) taught by Gerhart-Hines et al. and instant Compound 304 (SEQ ID NO: 3).
The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art. Therefore, claims 1-2, 7, 9, 12, and 18 are obvious over the cited art.
Regarding claims 13-14 and 21, Gerhart-Hines et al. teach that the conjugated moiety may be attached to the terminal amino acid, which includes via an amide bond with the N-terminal a-NH2 group. Gerhart-Hines et al. page 23, lines 5-33.
Regarding claim 15, Gerhart-Hines et al. teach that the peptide may C-terminal amidated. Gerhart-Hines et al. page 22, lines 16-20.
Regarding claim 28, Gerhart-Hines et al. teach pharmaceutical compositions comprising the Tac2 agonists and pharmaceutically acceptable carriers and excipients. Gerhart-Hines et al. page 24, line 22 - page 26, line 11.
Regarding claims 30-32, Gerhart-Hines et al. teach methods of treating insulin resistance, diabetes, and/or obesity comprising administering the Tac2 agonists. Gerhart-Hines et al. page 26, line 13 - page 32, line 35.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA MARCHETTI BRADLEY whose telephone number is (571)272-9044. The examiner can normally be reached Monday-Friday, 7 am - 3 pm.
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/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654
1 Not all of SEQ ID NOs: 1-57 fall within the scope of claim 1 for the reasons presented in the rejection under 35 U.S.C. 112(d) below.
2 Not all of SEQ ID NOs: 1-57 fall within the scope of claim 1 for the reasons presented in the rejection under 35 U.S.C. 112(d) below.
Prosecution Insights