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 of Group I and the species calcitonin in the reply filed on December 1, 2025, is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 17-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
The elected species calcitonin has been searched and is not free of the art or allowable.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825 because it does not contain a "Sequence Listing" as a separate part of the disclosure or a CRF of the “Sequence Listing.”.
Required response - Applicant must provide:
A "Sequence Listing" part of the disclosure; together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(a)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.821(a)(4); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(a)(3).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, 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.
If the "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, applicant must also provide:
A CRF in accordance with 37 CFR 1.821(e)(1) or 1.821(e)(2) as required by 1.825(a)(5); and
A statement according to item 2) a) or b) above.
Claim Interpretation
BRI of the claim term “modified peptide” encompasses any type of chemical or physical change to a peptide that yields a peptide with no or substantially reduced fibrillation and capability of forming a stable aqueous solution.
BRI of the claim limitation “no or substantially reduced fibrillation whereby said modified peptide produces a stable aqueous solution, due to said modification ” is a functional limitation. The aqueous solution is not required by the claim. Rather the claimed modified peptide must be capable for forming a stable aqueous solution. Further interpretation of this limitation is addressed in the 112(b) rejection below.
For the purposes of examination SEQ ID NO: 1 is defined according to Figure 12. Sequence compliance must be corrected (see above) and the indefiniteness rejection resolved (see below).
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 1-3, 5, 7-8, and 10 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.
BRI of the claim limitation “no or substantially reduced fibrillation whereby said modified peptide produces a stable aqueous solution, due to said modification ” is a functional limitation. The claim does not require a stable aqueous solution but rather the ability of the modified peptide to form a stable aqueous solution.
MPEP § 2173.05(g) states: Examiners should consider the following factors when examining claims that contain functional language to determine whether the language is ambiguous: (1) whether there is a clear cut indication of the scope of the subject matter covered by the claim; (2) whether the language sets forth well-defined boundaries of the invention or only states a problem solved or a result obtained; and (3) whether one of ordinary skill in the art would know from the claim terms what structure or steps are encompassed by the claim.
(1) Whether there is a clear cut indication of the scope of the subject matter covered by the claim.
Neither the specification nor the claims provide a limiting definition for “substantially reduced fibrillation” or “stable aqueous solution”. Although the specification provides means to measure fibrillation (ThioT fluorescence, visual inspection, and turbidity) and aqueous solution stability (Amide HDX-MS and CD spectroscopy), there is no quantitative cutoff provided for either relative term. In addition, there are no examples clearly and unambiguously designated as a “stable aqueous solution” and “unstable aqueous solution” that can serve as a point of comparison in the absence of a numerical measurement cut-off or definition.
(2) Whether the language sets forth well-defined boundaries of the invention or only states a problem solved or a result obtained
The specification does not define “stable aqueous solution”. The claim links stability to fibrillation but does not make it clear to what extent some fibrillation is permitted in a “stable aqueous solution” nor does the specification provide examples of stable and unstable aqueous solutions. It is not clear if “stable aqueous solution” requires a complete absence of fibrillation or whether some unknown level of fibrillation is permitted. It is not clear if “stable aqueous” solution is more stable than an aqueous solution formed by an unmodified peptide or if a higher standard is required.
(3) Whether one of ordinary skill in the art would know from the claim terms what structure or steps are encompassed by the claim.
The specification reduced to practice a single embodiment of the invention that reasonably appears to fall within the scope of the claims: phospho-Thr-13 hCT (full length human calcitonin phosphorylated at threonine 13). Phospho-Thr-13 hCT shows no significant change in ThioT fluorescence over time (Figure 8C) or turbidity signal over time (Figure 8D), and a clear solution by visual inspection suggesting no fibrillation under conditions known to yield fibrillation for unmodified human calcitonin (hCT). See also Tables 1 and 2. The specification states at para. [0095]: “Phosphorylation at Thr13 results in complete inhibition of fibrillation.” HDX-MS was performed for phospho-Thr-13 hCT under fibrillation stress conditions. Only as single peak consistent with monomeric peptide was observed with no peak broadening or change in peak position after 24 hours, no change in deuterium uptake or mass spectrum (Figure 10C). The specification states at para. [0097] that these results indicate “the absence of oligomers or fibrillar intermediates.” Under conditions that produce fibrillation in hCT, Phospho-Thr-13 hCT shows no change in CD spectrum for 24 hours, indicating no fibrillation (Figure 11A). Taken together, these data indicate that Phospho-Thr-13 hCT is a modified peptide that has no or substantially reduced fibrillation whereby said modified peptide produces a stable aqueous solution (complete absence of fibrillation) due to said modification.
In contrast, the specification reduces to practice two modified peptides that meet the structural limitations of the claim but for which it is unclear whether the functional limitations of the claim are met (para. [0094]-[0101]):
Phospho-Ser-5 hCT shows a change in ThioT fluorescence over time indicating fibrillation (Figure 8A), a shorter lag time (58 + 8 min vs 172 + 15 min, Tables 1 and 2), a 10-fold lower ThioT fluorescence intensity (Figure 8A vs 9A), a significantly lower turbidity signal intensity (Figures 8B vs 9B), and a thin translucent film vs solid dense deposits by visual inspection compared to hCT. The specification states at para. [0095]: “The weaker ThioT and turbidity intensities along with the nature of oligomeric deposits, suggest that the phosphorylation of Ser5 interferes with fibrillation but does not prevent it.”
Phospho-Thr-21 hCT shows a change in ThioT fluorescence over time (Figure8E), a much greater fibrillation lag time (568 + 95 min vs 172 + 15 min, Tables 1 and 2) with no plateau within 24 hours, a similar ThioT fluorescence intensity (Figure 8E vs 9A), a similar turbidity signal intensity (Figures 8F vs 9B), and a clear solution by visual inspection compared to hCT. The specification states at para. [0095]: “For phospho-Thr-21 hCT, the greater lag time and incomplete growth phase suggest that phosphorylation of Thr21 delays fibril formation and growth, but again does not prevent it entirely.”
Taken together, these data indicate that Phospho-Ser-5 hCT and Phospho-Thr-21 hCT are modified peptides with reduced or interfered with fibrillation. It is not clear whether Phospho-Ser-5 hCT and Phospho-Thr-21 hCT are included in the scope of the claims because given the improvement in fibrillation relative to hCT, aqueous solutions formed by these peptides are considered stable, or whether Phospho-Ser-5 hCT and Phospho-Thr-21 hCT are excluded from the scope of the claims because since fibrillation occurs at all, the aqueous solutions formed by these peptides are not considered to be stable. The ambiguity is underscored by dependent claim 5 and 10 which appear to include these modified in the scope of the genus and the contradictory data in the specification.
This ambiguity makes it difficult for one of ordinary skill in the art to know from the claim terms what structures are encompassed by the claim. For example, the prior art of Zurdo et al. (WO 2005/035566 A1) teaches modified calcitonin peptides whose self-aggregation activity is lower than native human calcitonin (p. 3, lines 10-14; Figure 1). The modified calcitonin peptides have increased solubility and/or a reduced propensity or tendency to self-aggregate in aqueous solution (p. 7, lines 4-7; Example 2 on pp. 30-31). Specifically the 5p and 6s variants (SEQ ID NOs: 4 and 5 in Example 1) show a slower rate of aggregation and lower degree of aggregation and higher recovery of soluble peptide from solution (Example 2). It is not clear whether the 5p and 6s variants are included in the scope of the claims because given the improvement in fibrillation relative to hCT, aqueous solutions formed by these peptides are considered stable, or whether the 5p and 6s variants are excluded from the scope of the claims because since fibrillation occurs at all, the aqueous solutions formed by these peptides are not considered to be stable.
In summary, in independent claims 1 and 7, the indefinite language is: “wherein said modified peptide has no or substantially reduced fibrillation whereby said modified peptide produces a stable aqueous solution, due to said modifications.” The language is indefinite because two or more plausible constructions exist for the function limitation: 1) no fibrillation is required in a stable aqueous solution, or 2) some extent of fibrillation is permitted in a stable aqueous solution but a reduction occurs relative to the unmodified form of the peptide. Because of this ambiguity, it is not clear which modified peptides are included in the claim and which are excluded on the basis of function.
Dependent claims 2-3, 5, 8 and 10 fail to remedy this issue and are likewise rejected.
Claims 3, 5, 8, and 10 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.
The indefinite language is SEQ ID NO: 1 (human calcitonin). The language is indefinite because no sequence listing has been filed. In addition, it is unclear whether the limitation in parentheses is part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 2, and 7 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more.
Regarding claim1, BRI of claims 1, 2, and 7 includes the nature-based tau K18 fragment, which may be phosphorylated at numerous positions, as evidenced by Haj-Yahya et al. (Site-specific hyperphosphorylation of tau inhibits its fibrillization in vitro, blocks its seeding capacity in cells, and disrupts its microtubule binding; Implications for the native state stabilization of tau. bioRxiv 772046; doi: https://doi.org/10.1101/772046, published September 18, 2019), and the nature-based carrier water. Haj-Yahya et al. teach that phosphorylation at three residues (pS356, pS262 and pS258) completely abolishes fibril formation (p. 12, para. 1). Because the art teaches that fibrillation is completely abolished, aqueous solutions containing these modified peptides are considered to be stable.
Step 1: Claims 1-2 and 7 are to a composition of matter.
Step 2A, Prong 1: Claims 1-2 and 7 are directed to a product of nature, the phosphorylate peptide tau K18 and the nature-based product water. Because the peptide and water as claimed are not found together in nature, the closest counterpart to the nature-based products is phosphorylated peptide tau K18 and water. The claimed peptide is different, but not markedly different from tau K18, which may be phosphorylated in nature, as evidenced by Haj-Yahya et al. Phosphorylation at three residues (pS356, pS262 and pS258) disrupts fibril formation. Stability in aqueous solution is innate to the peptide sequence itself. There is no evidence on record that mixing the claimed peptide with water changes the structure, function, or other properties of either the peptide or water in a marked way. Thus, for at least one embodiment of the claim with the BRI (e.g. wherein the carrier is water), the claimed mixture as whole does not display markedly different characteristics compared to the naturally-occurring counterparts. Instead, the peptide and water have the same characteristics in the mixture as the individual components, the same chemical structure and the same function and being a solvent. See Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 130, 76 USPQ 280, 281 (1948). Accordingly, each component, the peptide and the carrier, is a natural phenomenon exception.
Step 2A, Prong 2: The claim only recites the peptide and the carrier, which are natural phenomenon exceptions. Because there are no additional claim elements besides the judicial exceptions, the judicial exceptions are not integrated into a practical application (MPEP § 2106.04(d)(III)). In addition, because the limitation “pharmaceutically acceptable” does not actually provide a treatment or prophylaxis, e.g., it is merely an intended use of the claimed invention or a field of use limitation, then it cannot integrate a judicial exception under the "treatment or prophylaxis" consideration (MPEP § 2106.04(d)(2)).
Step 2B: Prior to applicant’s invention and at the time of filing the application, using a carrier for a peptide was well-understood, routine, and conventional. Because mixing the peptide with a carrier at this high level of generality does not meaningfully limit the claim, the claim does not amount to significantly more than the judicial exception (MPEP § 2106.05). In addition, because the limitation “pharmaceutically-acceptable” does not actually provide a treatment or prophylaxis, e.g., it is merely an intended use of the claimed invention or a field of use limitation, then it cannot integrate a judicial exception under the "treatment or prophylaxis" consideration (MPEP § 2106.04(d)(2)).
Therefore, claims 1-2 and 7 are patent ineligible.
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 1-3, 5, 7-8 and 10 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.
BRI of claim 1 is based on structural and function limitations.
Structural: BRI of the claim term “modified peptide” encompasses any type of chemical or physical change to a peptide.
Functional: BRI of the claim limitation “no or substantially reduced fibrillation whereby said modified peptide produces a stable aqueous solution, due to said modification ” does not require a stable aqueous solution but rather the ability of the peptide to form a stable aqueous solution. BRI of stable aqueous solution in the instant claims is linked to fibrillation (see rejection under 35 U.S.C. 112(b) above). The claim is broad with respect to aqueous conditions and excipients, storage conditions, and storage time.
Claims 2 and 7 limit the modification to phosphorylation.
Claims 3, 5, 8, and 10 limit the peptide to human calcitonin and fragments thereof. Claims 5 and 10 limit the site of phosphorylation.
Only those modified peptides meeting the structural and functional requirements of the genus are encompassed by the claims. Therefore, the claim encompasses all of the sequences meeting the structural requirements that also have no or substantially reduced fibrillation and an ability to produce a stable aqueous solution.
Despite the breadth of the claims, the specification reduces to practice only a single embodiment that unambiguously falls within the scope of the invention: phospho-Thr-13 hCT (full length human calcitonin phosphorylated at threonine 13). Phospho-Thr-13 hCT shows no significant change in ThioT fluorescence over time (Figure 8C) or turbidity signal over time (Figure 8D), and a clear solution by visual inspection suggesting no fibrillation under conditions known to yield fibrillation for unmodified human calcitonin (hCT). See also Tables 1 and 2. The specification states at para. [0095]: “Phosphorylation at Thr13 results in complete inhibition of fibrillation.” HDX-MS was performed for phospho-Thr-13 hCT under fibrillation stress conditions. Only as single peak consistent with monomeric peptide was observed with no peak broadening or change in peak position after 24 hours, no change in deuterium uptake or mass spectrum (Figure 10C). The specification states at para. [0097] that these results indicate “the absence of oligomers or fibrillar intermediates.” Under conditions that produce fibrillation in hCT, Phospho-Thr-13 hCT shows no change in CD spectrum for 24 hours, indicating no fibrillation (Figure 11A). Taken together, these data indicate that Phospho-Thr-13 hCT is a modified peptide that has no or substantially reduced fibrillation whereby said modified peptide produces a stable aqueous solution due to said modification.
In contrast, the specification reduces to practice two modified peptides that meet the structural limitations of the claim but for which it is unclear whether the functional limitations are met (para. [0094]-[0101]):
Phospho-Ser-5 hCT shows a change in ThioT fluorescence over time indicating fibrillation (Figure 8A), a shorter lag time (58 + 8 min vs 172 + 15 min, Tables 1 and 2), a 10-fold lower ThioT fluorescence intensity (Figure 8A vs 9A), a significantly lower turbidity signal intensity (Figures 8B vs 9B), and a thin translucent film vs solid dense deposits by visual inspection compared to hCT. The specification states at para. [0095]: “The weaker ThioT and turbidity intensities along with the nature of oligomeric deposits, suggest that the phosphorylation of Ser5 interferes with fibrillation but does not prevent it.”
Phospho-Thr-21 hCT shows a change in ThioT fluorescence over time (Figure8E), a much greater fibrillation lag time (568 + 95 min vs 172 + 15 min, Tables 1 and 2) with no plateau within 24 hours, a similar ThioT fluorescence intensity (Figure 8E vs 9A), a similar turbidity signal intensity (Figures 8F vs 9B), and a clear solution by visual inspection compared to hCT. The specification states at para. [0095]: “For phospho-Thr-21 hCT, the greater lag time and incomplete growth phase suggest that phosphorylation of Thr21 delays fibril formation and growth, but again does not prevent it entirely.”
Taken together, these data indicate that Phospho-Ser-5 hCT and Phospho-Thr-21 hCT are modified peptides with reduced or interfered with fibrillation. It is not clear whether because fibrillation occurs at all, the aqueous solutions formed by these modified peptides are considered to be stable.
As discussed above the claim scope is potentially enormous depending on how many of the modified peptides that meet the structural requirements are also able to have no or substantially reduced fibrillation and form a stable aqueous solution; in comparison, the scope of the description which only includes one or at most three species, is extremely narrow. The actual reduction to practice does not include species characterized by any modification other than phosphorylation or any peptide other than full-length human calcitonin of SEQ ID NO: 1. Therefore, one of ordinary skill in the art would not consider Phospho-Thr-13 (and possibly hCT Phospho-Ser-5 hCT and Phospho-Thr-21 hCT) to be representative of the full scope of the claimed genus.
The data presented in the specification raise more questions about the physical properties of the genus than they answer. The data do not suggest the physical basis fibrillation and aqueous solution stability and therefore do not describe which modifications, at which positions, and to which peptides could be made while preserving the property of having no or substantially reduced fibrillation and forming a stable aqueous solution. Understanding the physical basis for fibrillation and aqueous solution stability 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 specification does not describe a general correlation between structure and function for the claimed genus. Even for human calcitonin, the role of each amino acid in fibrillation and aqueous solution stability are not described. As a result, it is impossible to predict, based on the specification, how changing any position will affect the property of having no or substantially reduced fibrillation and forming a stable aqueous solution.
Solid state peptide synthesis and the cloning, recombinant expression and purification of proteins is well-known in the art. It is not disputed that one of ordinary skill in the art could isolate, albeit with route experimentation and optimization, a modified peptide of a given sequence provided that the sequence is known. Where the specification fails to provide description is in the structure of the peptide to make.
The data in the specification underscore the high level of unpredictability in the art. Even for a single peptide, human calcitonin, and a single type of modification, phosphorylation, empirical evidence and experimentation is required to determine if a modified peptide falls within the scope of the claim. Even then, given the ambiguity in the specification, the empirical evidence may be inconclusive. These results are consistent with the prior art of Zurdo et al. (WO 2005/035566 A1). Zurdo et al. teach modified calcitonin peptides whose self-aggregation activity is lower than native human calcitonin (p. 3, lines 10-14; Figure 1). The modified calcitonin peptides have increased solubility and/or a reduced propensity or tendency to self-aggregate in aqueous solution (p. 7, lines 4-7; Example 2 on pp. 30-31). Specifically the 5p and 6s variants (SEQ ID NOs: 4 and 5 in Example 1) show a slower rate of aggregation and lower degree of aggregation and higher recovery of soluble peptide from solution (Example 2). Although the modified peptides are improved compared to the unmodified calcitonin, it is not clear if aqueous solutions formed by the 5p and 6s variants are stable given that a significant degree of aggregation still occurs (i.e. Table 1 shows that over 50% of the peptide aggregates in solution).
These observations are supported by the prior art which also shows a high level of unpredictability and complexity associated with phosphorylation and fibrillation of peptides in general. Although the prior art includes several peptides for which phosphorylation inhibits fibrillation and yields a stable aqueous solution (e.g. glucagon as evidenced by Murphy Topp et al. and tau K18 as evidenced by Haj-Yahya et al.), the prior art more generally describes a complex picture with phosphorylation tending to lead to an increase in fibrillation. Inoue et al. teach that hyperphosphorylated forms of tau protein are the main component of paired helical filaments of neurofibrillary tangles in the brain of Alzheimer’s disease patients, suggesting that phosphorylation can cause fibrillation (abstract). Hu et al. teach on p. 1 that “Pathological aggregation of amyloid proteins such as α-synuclein (α-syn) and Tau is strongly linked to neurodegenerative diseases (NDs). Numerous posttranslational modifications (PTMs), such as phosphorylation, O-glycosylation, ubiquitination, and acetylation, have been identified on amyloid proteins, playing diverse roles in regulating protein conformation, aggregation kinetics, fibril structures and pathology.” Hu et al. show that different modifications at the same site of the same protein can yield different unpredictable effects on fibrillation (abstract). See also Zapadka et al., especially section 2.5, which reviews the effect of post-translation modification on fibrillation in therapeutic peptides. Given this complexity, the prior art does not present clear rules to distinguish modifications that can yield no or substantially reduced fibrillation and a stable aqueous solution from those that are not capable of this function.
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 1-3, 5, 7-8, and 10 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 making and using Phospho-Thr-13 hCT, does not reasonably provide enablement for making and using all other modified peptides. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or 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 pertains to modified peptides with altered levels of fibrillation and aqueous solution stability.
The breadth of the claims
BRI of claim 1 is based on structural and function limitations.
Structural: BRI of the claim term “modified peptide” encompasses any type of chemical or physical change to a peptide.
Functional: BRI of the claim limitation “no or substantially reduced fibrillation whereby said modified peptide produces a stable aqueous solution, due to said modification ” does not require a stable aqueous solution but rather the ability of the peptide to form a stable aqueous solution. BRI of stable aqueous solution in the instant claims is linked to fibrillation (see rejection under 35 U.S.C. 112(b) above). The claim is broad with respect to aqueous conditions and excipients, storage conditions, and storage time.
Claims 2 and 7 limit the modification to phosphorylation.
Claims 3, 5, 8, and 10 limit the peptide to human calcitonin and fragments thereof. Claims 5 and 10 limit the site of phosphorylation.
Only those modified peptides meeting the structural and functional requirements of the genus are encompassed by the claims. Therefore, the claim encompasses all of the sequences meeting the structural requirements that also have no or substantially reduced fibrillation and an ability to produce a stable aqueous solution.
The State of the Prior Art and Level of Predictability
The data in the specification underscore the high level of unpredictability in the art. Even for a single peptide, human calcitonin, and a single type of modification, phosphorylation, empirical evidence and experimentation is required to determine if a modified peptide falls within the scope of the claim. Even then, given the ambiguity in the specification, the empirical evidence may be inconclusive. These results are consistent with the prior art of Zurdo et al. (WO 2005/035566 A1). Zurdo et al. teach modified calcitonin peptides whose self-aggregation activity is lower than native human calcitonin (p. 3, lines 10-14; Figure 1). The modified calcitonin peptides have increased solubility and/or a reduced propensity or tendency to self-aggregate in aqueous solution (p. 7, lines 4-7; Example 2 on pp. 30-31). Specifically the 5p and 6s variants (SEQ ID NOs: 4 and 5 in Example 1) show a slower rate of aggregation and lower degree of aggregation and higher recovery of soluble peptide from solution (Example 2). Although the modified peptides are improved compared to the unmodified calcitonin, it is not clear if aqueous solutions formed by the 5p and 6s variants are stable given that a significant degree of aggregation still occurs (i.e. Table 1 shows that over 50% of the peptide aggregates in solution).
These observations are supported by the prior art which also shows a high level of unpredictability and complexity associated with phosphorylation and fibrillation of peptides in general. Although the prior art includes several peptides for which phosphorylation inhibits fibrillation and yields a stable aqueous solution (e.g. glucagon as evidenced by Murphy Topp et al. and tau K18 as evidenced by Haj-Yahya et al.), the prior art more generally describes a complex picture with phosphorylation tending to lead to an increase in fibrillation. Inoue et al. teach that hyperphosphorylated forms of tau protein are the main component of paired helical filaments of neurofibrillary tangles in the brain of Alzheimer’s disease patients, suggesting that phosphorylation can cause fibrillation (abstract). Hu et al. teach on p. 1 that “Pathological aggregation of amyloid proteins such as α-synuclein (α-syn) and Tau is strongly linked to neurodegenerative diseases (NDs). Numerous posttranslational modifications (PTMs), such as phosphorylation, O-glycosylation, ubiquitination, and acetylation, have been identified on amyloid proteins, playing diverse roles in regulating protein conformation, aggregation kinetics, fibril structures and pathology.” Hu et al. show that different modifications at the same site of the same protein can yield different unpredictable effects on fibrillation (abstract). See also Zapadka et al., especially section 2.5, which reviews the effect of post-translation modification on fibrillation in therapeutic peptides. Given this complexity, the prior art does not present clear rules to distinguish modifications that can yield no or substantially reduced fibrillation and a stable aqueous solution from those that are not capable of this function.
The Level of Guidance in the Specification
The data presented in the specification raise more questions about the physical properties of the genus than they answer. The data do not suggest the physical basis fibrillation and aqueous solution stability and therefore do not describe which modifications, at which positions, and to which peptides could be made while preserving the property of having no or substantially reduced fibrillation and forming a stable aqueous solution. Understanding the physical basis for fibrillation and aqueous solution stability 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 specification does not describe a general correlation between structure and function for the claimed genus. Even for human calcitonin, the role of each amino acid in fibrillation and aqueous solution stability are not described. As a result, it is impossible to predict, based on the specification, how changing any position will affect the property of having no or substantially reduced fibrillation and forming a stable aqueous solution
The Presence or Absence of Working Examples
Despite the breadth of the claims, the specification reduces to practice only a single embodiment that unambiguously falls within the scope of the invention: phospho-Thr-13 hCT (full length human calcitonin phosphorylated at threonine 13). Phospho-Thr-13 hCT shows no significant change in ThioT fluorescence over time (Figure 8C) or turbidity signal over time (Figure 8D), and a clear solution by visual inspection suggesting no fibrillation under conditions known to yield fibrillation for unmodified human calcitonin (hCT). See also Tables 1 and 2. The specification states at para. [0095]: “Phosphorylation at Thr13 results in complete inhibition of fibrillation.” HDX-MS was performed for phospho-Thr-13 hCT under fibrillation stress conditions. Only as single peak consistent with monomeric peptide was observed with no peak broadening or change in peak position after 24 hours, no change in deuterium uptake or mass spectrum (Figure 10C). The specification states at para. [0097] that these results indicate “the absence of oligomers or fibrillar intermediates.” Under conditions that produce fibrillation in hCT, Phospho-Thr-13 hCT shows no change in CD spectrum for 24 hours, indicating no fibrillation (Figure 11A). Taken together, these data indicate that Phospho-Thr-13 hCT is a modified peptide that has no or substantially reduced fibrillation whereby said modified peptide produces a stable aqueous solution due to said modification.
In contrast, the specification reduces to practice two modified peptides that meet the structural limitations of the claim but for which it is unclear whether the functional limitations are met (para. [0094]-[0101]):
Phospho-Ser-5 hCT shows a change in ThioT fluorescence over time indicating fibrillation (Figure 8A), a shorter lag time (58 + 8 min vs 172 + 15 min, Tables 1 and 2), a 10-fold lower ThioT fluorescence intensity (Figure 8A vs 9A), a significantly lower turbidity signal intensity (Figures 8B vs 9B), and a thin translucent film vs solid dense deposits by visual inspection compared to hCT. The specification states at para. [0095]: “The weaker ThioT and turbidity intensities along with the nature of oligomeric deposits, suggest that the phosphorylation of Ser5 interferes with fibrillation but does not prevent it.”
Phospho-Thr-21 hCT shows a change in ThioT fluorescence over time (Figure8E), a much greater fibrillation lag time (568 + 95 min vs 172 + 15 min, Tables 1 and 2) with no plateau within 24 hours, a similar ThioT fluorescence intensity (Figure 8E vs 9A), a similar turbidity signal intensity (Figures 8F vs 9B), and a clear solution by visual inspection compared to hCT. The specification states at para. [0095]: “For phospho-Thr-21 hCT, the greater lag time and incomplete growth phase suggest that phosphorylation of Thr21 delays fibril formation and growth, but again does not prevent it entirely.”
Taken together, these data indicate that Phospho-Ser-5 hCT and Phospho-Thr-21 hCT are modified peptides with reduced or interfered with fibrillation. It is not clear whether because fibrillation occurs at all, the aqueous solutions formed by these modified peptides are considered to be stable.
As discussed above the claim scope is potentially enormous depending on how many of the modified peptides that meet the structural requirements are also able to have no or substantially reduced fibrillation and form a stable aqueous solution; in comparison, the scope of the description which only includes one or at most three species, is extremely narrow. The actual reduction to practice does not include species characterized by any modification other than phosphorylation or any peptide other than full-length human calcitonin of SEQ ID NO: 1. Therefore, one of ordinary skill in the art would not consider Phospho-Thr-13 (and possibly hCT Phospho-Ser-5 hCT and Phospho-Thr-21 hCT) to be representative of the full scope of the claimed genus.
The Quantity of Experimentation Necessary
Considering the factors above, the skilled artisan would be burdened with undue experimentation in determining if a modified peptide would have no or substantially reduced fibrillation and form a stable aqueous solution. The skilled artisan would be burdened with testing a broad range of modifications for every possible peptide in in vitro fibrillation and stability assays. The stable modified peptides would then have to be subjected to assays for activity to determine if a relevant use, therapeutic or otherwise, can be found. 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 § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-2 and 7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Murphy Topp et al. (US 2018/0298076 A1).
Regarding claim 1, Murphy Topp et al. teach modified glucagon molecules that are soluble in an aqueous solution. The modification of amino acids in the glucagon prevent their interaction and inhibit fibril formation (para. [0006]-[0007]). Murphy Topp et al. demonstrate in Examples 2 and 3 that the modified glucagon has no or substantially no fibrillation as monitored by ThT fluorescence and turbidity and in Example 6 that the modified glucagons are chemically stable when stored for ten days at 5° C., 23° C. and 37° C.
Regarding claim 2, Murphy Topp et al. teach that the modification is phosphorylation of one or more side chains of glucagon (para. [0008]; Examples 2, 3, and 6).
Regarding claim 7, Murphy Topp et al. teach pharmaceutical compositions comprising the modified glucagon and a pharmaceutically-acceptable carrier (para. [0052]).
Claims 1-2 and 7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Haj-Yahya et al. (Site-specific hyperphosphorylation of tau inhibits its fibrillization in vitro, blocks its seeding capacity in cells, and disrupts its microtubule binding; Implications for the native state stabilization of tau. bioRxiv 772046; doi: https://doi.org/10.1101/772046, published September 18, 2019).
Regarding claim 1, Haj-Yahya et al. teach modified tau K18 fragment peptide that is soluble in an aqueous solution. The modification of amino acids in the K18 fragment peptide completely abolishes fibril formation (p. 12, para. 1).
Regarding claim 2, Haj-Yahya et al. teach that the modification is phosphorylation at three residues (pS356, pS262 and pS258) (p. 12, para. 1).
Regarding claim 7, Haj-Yahya et al. teach the peptides in aqueous solution, which is pharmaceutically-acceptable (p. 12, para. 1).
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zurdo et al. (WO 2005/035566 A1).
Zurdo et al. teach modified calcitonin peptides whose self-aggregation activity is lower than native human calcitonin (p. 3, lines 10-14; Figure 1). The modified calcitonin peptides have increased solubility and/or a reduced propensity or tendency to self-aggregate in aqueous solution (p. 7, lines 4-7; Example 2 on pp. 30-31). Specifically the 5p and 6s variants (SEQ ID NOs: 4 and 5 in Example 1) show a slower rate of aggregation and lower degree of aggregation and higher recovery of soluble peptide from solution (Example 2).
The 5p and 6s variants are included in the scope of instant claim 1 based on the construction that “stable aqueous solution” includes improvement in fibrillation relative to hCT and improvement in aqueous solution stability relative to hCT.
Conclusion
No claims are allowed.
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/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654