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 .
Status of the Application
The claims of 2 December 2022 are entered.
The Election of 4 February 2026 is entered.
Claims 4, 9-13, 17, 18, 20, 23, 25-27, 29, 34, 35, 37, and 39 have been canceled. Claims 1-3, 5-8, 14-16, 19, 21, 22, 24, 28, 30-33, 36, and 38 are pending. Claims 19, 21, 22, 24, and 28 are withdrawn without traverse. Claims 1-3, 5-8, 14-16, 30, 32, 33, 36, and 38 are being examined on the merits.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-3, 5-8, 14-16, 30, 32, 33, 36, and 38), SEQ ID NO: 32, and –(CH2)3-CH=CH-(CH2)3- in the reply filed on 4 February 2026 is acknowledged.
Claims 19, 21, 22, 24, and 28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4 February 2026.
A search of SEQ ID NO: 32 indicates it is free of the art. Accordingly, the search has been extended to other members of the genus, rejections for which are provided below.
Claim Rejections - 35 USC § 112
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, 5-8, 14-16, 30, 32, 33, 36, and 38 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 a compound of formula (I) and salts thereof, does not reasonably provide enablement for solvates of the same compound. 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 the invention commensurate in scope with these claims.
“[T]o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation.’” Genentech Inc. v. Novo Nordisk 108 F.3d 1361, 1365, 42 USPQ2d 1001, 1004 (Fed. Cir. 1997); In re Wright 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); See also Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 1212, 18 USPQ2d 1016, 1026 (Fed. Cir. 1991); In re Fisher 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Further, in In re Wands 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) the court stated:
Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman [230 USPQ 546, 547 (BdPatAppInt 1986)]. They 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 unpredict-ability of the art, and (8) the breadth of the claims.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Nature of the Invention
The invention is drawn to compounds of formula (I) encompassing a 14-mer stapled peptide, including salts and solvates thereof.
Breadth of the Claims
The claims are broad with respect to the compound and the solvate forms.
State of the Prior Art
VIPPAGUNTA (Vippagunta, et al. Adv. Drug Delivery Rev. (2001) 48, pages 3-26) teaches that, "The common crystalline forms found for a given drug substance are polymorphs and solvates. Crystalline polymorphs have the same chemical composition, but different internal crystal structures, and therefore, possess different physico-chemical properties." (page 4).
"Solvates, also known as pseudopolymorphs, are crystalline solid adducts containing solvent molecules within the crystal structure, ... giving rise to unique differences in the physical and pharmaceutical properties of the drug. If the incorporated solvate is water, a solvate is termed a hydrate." (page 4).
Vippagunta teaches that, "Because different crystalline polymorphs and solvates differ in crystal packing, and/or molecular conformation as well as in lattice energy and entropy, there are usually significant differences in their physical properties, such as density, hardness, tabletability, refractive index, melting point, enthalpy of fusion, vapor pressure, solubility, dissolution rate, other thermodynamic and kinetic properties and even color. Differences in physical properties of various solid forms have an important effect on the processing of drug substances into drug products, while differences in solubility may have implications on the absorption of the active drug from its dosage form, by affecting the dissolution rate and possibly the mass transport of the molecules." (page 4).
Vippagunta teaches that, "It is very important to control the crystal form of the drug during the various drug development, because any phase change due to polymorph interconversions, desolvation of solvates, formation of hydrates and change in the degree of crystallinity can alter the bioavailability of the drug. When going through a phase transition, a solid drug may undergo a change in its thermodynamic properties, with consequent changes in its dissolution and transport characteristics." (page 5).
Vippagunta teaches that there are reversible and irreversible polymorphs (page 6), and polymorphs which are structural or conformational polymorphs (pages 7-11). Vippagunta further teaches that, "The main challenge in managing the phenomenon of multiple solid forms of a drug is the inability to predict the number of forms that can be expected in a given case." (page 11).
Vippagunta teaches that "Phase changes due to hydration/dehydration and solvation/desolvation of pharmaceutical compounds during processing or in the final product may result in an unstable system that would effect the bioavailability of drug from solid dosage forms. Various types of phase changes are possible in solid-state hydrated or solvated systems in response to changes in environmental conditions... For example, some hydrated compounds may convert to an amorphous phase upon dehydration and some may convert from a lower to a higher state of hydration yielding forms with lower solubility. Alternatively, a kinetically favored but thermodynamically unstable form may be converted during pharmaceutical processing to a more stable and less soluble form." (page 17).
Vippagunta teaches that, "Predicting the formation of solvates or hydrates of a compound and the number of molecules of water or solvent incorporated into the crystal lattice of a compound is complex and difficult Each solid compound responds uniquely to the possible formation of solvates or hydrates and hence generalizations cannot be made for a series of related compounds... There may be too many possibilities so that no computer programs are currently available for predicting the crystal structures of hydrates and solvates." (page 18).
Relative Skill of those in the Art
The relative skill of those in the art is high.
Predictability or Unpredictability of the Art
There is a general lack of predictability in the pharmaceutical art. In re Fisher, 427, F. 2d 833, 166, USPQ 18 (CCPA 1970).
As indicated above, Vippagunta indicates a level of unpredictability as concerning solvates of a given drug.
Amount of Direction or Guidance Given
The specification guides that solvates “…include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates, and the like”. This guidance leaves the solvate form open-ended given the “and the like” so that the claims can conceivably encompass any solvate form.
Presence/Absence of Working Examples
No working examples concern solvate formation.
Quantity of Experimentation Necessary
The specification offers little concrete guidance on solvates. The prior art indicates the field is unpredictable. There are no examples showing production of a solvate. It would require undue experimentation for one of ordinary skill in the art to arrive at any and all solvates of the any of the compounds presently claimed, absent some teaching or suggestion in the specification of the stepwise approach to arrive at such, which was not found to be described, based on the uncertainty in the art (Vippagunta evidences) in arriving at solvates of lead compounds, including the prodrugs presently claimed.
In view of the Wands factors as discussed above, it is the Examiner’s opinion that the claims are not fully enabled and one of skill in the art would have to engage in undue experimentation to practice the invention as claimed herein, without a reasonable assurance of success.
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.
Claim 16 is 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.
Claim 16 recites “Asp Thr Leu Ala (SEQ ID NO: 40)”. This is indefinite because it does not match the disclosed sequence as found in SEQ ID NO: 40. Accordingly, one of ordinary skill in the art cannot ascertain the metes and bounds of the claim as written.
Claim 16 also recites “Val Val Thr Arg Arg Cys Leu His Arg Cys Phe Asp Thr Leu Ala (SEQ ID NO: 51)”. However, SEQ ID NO: 51 as found in the CRF of 2 December 2022 is a nucleotide sequence “gacaagcttg cgatgttttc cggtggcggc ggcccgc”. Given this discrepancy, the skilled artisan cannot determine if the claim is limited to a nucleotide or an amino acid sequence and therefore the metes and bounds are unclear.
The Examiner suggests insertion of the entire sequence of SEQ ID NO: 40 to overcome this rejection.
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 16 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. Claim 16 recites that one of the options is Asp Thr Leu Ala (SEQ ID NO: 40), which fails to further limit claim 1 since it is a tetrapeptide while claim 1 requires at least a 14-mer. SEQ ID NO: 51 fails to further limit claim 1 since it recites a sequence with no positions available for linking as found in claim 1. As written, SEQ ID NO: 51 is a linear peptide without any stapling present in the sequence. 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.
It appears based upon the submitted sequence as found in SEQ ID NO: 40 that this may be an error in formatting within the claim language since the claimed sequence does not match the disclosed SEQ ID.
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.
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 1-3, 5, 6, 8, 14, 16, 30, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Matthews et al. (US 5,859,187 A, published 12 January 1999, hereafter referred to as ‘187) and Walensky L and Bird G (J. Med. Chem. 57:6275-6288, published 19 February 2014, hereafter referred to as Walensky).
The ‘187 patent discloses a peptide of SEQ ID NO: 11 that is identical from residues 2-15 to SEQ ID NO:1 as instantly claimed (see e.g. claim 10). The residues are taken from the C-terminus of HSV DNA polymerase that can inhibit the UL42 stimulation of the polymerase (see e.g. Col. 1 lines 32-40).
The difference between ‘187 and the claimed invention is that ‘187 does not disclose or suggest stapling of the peptide.
Walensky discloses that peptide stapling can stabilize helical structures that increase resistance to proteolysis (see e.g. p.6275). Walensky suggests that knowledge that a peptide naturally forms a helix is highly useful as a starting point (see e.g. p.6277). Walensky suggests using i, i+4 and i, i+7 pairs (see e.g. p.6277).
The structure of SEQ ID NO: 11 of ‘187 was known in the art to form a helical structure naturally, as evidenced by the crystal structure of HSV-1 UL42 bound to the C-terminus of HSV polymerase as found in PDB structure 1DML:
PNG
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132
510
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Greyscale
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92
1390
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Greyscale
.
It would have been obvious to one of ordinary skill in the art before the effective filing date given that the sequence of ‘187 naturally forms a helix when in complex with its binding partner, and given that one would seek to stabilize the peptide by applying the helical stapling process suggested by Walensky for known helices using peptide staples at i, i+4 and/or i, i+7 positions. The rationale comes from ‘187 already laying forth the peptide sequence as a useful inhibitor for disrupting polymerase activity in HSV, combined with the evidence from the art showing that it was known to form a helix along with Walensky noting that knowledge of natural helix formation was especially helpful for stapling to stabilize peptides. There would have been a reasonable expectation of success because the peptide was known in the art, the helical structure was known, and the skilled artisan merely would have had to apply the stapling techniques of Walensky to a target meeting the requirements laid out by Walensky. The invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
With respect to claim 2, the Walensky art describes a common single staple between R5 and S5 linkers resulting in a (CH2)3-CH=CH-(CH2)3 linker (see e.g. Figure 3).
With respect to claim 3, following the Walensky protocol for i, i+4 or i, i+7 scanning stapling would result in the claimed residue pairs including the (CH2)3-CH=CH-(CH2)3 linker.
With respect to claim 5, ‘187 as discussed above discloses H-Glu-Glu-Thr-Arg-Arg-Met-Leu-His-Arg-Ala-Phe-Asp-Thre-Leu-Ala-OH, where Xaa1 is Glu, Xaa2 is Thr, Xaa3 is Arg, Xaa4 is Arg, Xaa5 is Met, Xaa6 is Leu, Xaa7 is His, Xaa8 is Arg, Xaa9 is Ala, Xaa10 is Phe, Xaa11 is Asp, Xaa12 is Thr, and Xaa13 is Leu, and Xaa14 is Ala.
With respect to claim 6, the specification offers no particular definition of “consists essentially of”. Per MPEP 2111.03 III., “For the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, "consisting essentially of" will be construed as equivalent to "comprising."” As there is no indication as to what the basic and novel characteristics of the invention are, the claim is construed as equivalent to “comprising” and therefore the above ‘187 and Walensky art applies.
With respect to claim 8, as set forth above the ‘187 art includes a N-terminal Glu residue, satisfying option (c).
With respect to claim 15, as set forth above the Walensky art provides motivation to scan for i, i+4 staples. Walensky also offers S-pentenylalanine stapling (see e.g. p.6277, Figure 3).
With respect to claim 16, at least SEQ ID NO: 2 is rendered obvious by ‘187 and Walensky.
With respect to claim 30, the ‘187 art indicates application via a parenteral route, which by necessity requires an applicator such as a syringe (see e.g. Col.2 lines 29-36). Per MPEP 2112.01 III., the instructional materials are non-functional printed matter that does not distinguish the claims from the prior art.
With respect to claim 32, ‘187 suggests compositions for parenteral administration with a carrier, which requires that they be pharmaceutical compositions (see e.g. Col.2 lines 46-55).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY J MIKNIS whose telephone number is (571)272-7008. The examiner can normally be reached M-F 9-5.
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/ZACHARY J MIKNIS/Patent Examiner, Art Unit 1658