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 Group III (i.e., claims 84-99 drawn to a composition comprising a synthetic peptide shuttle agent covalently conjugated to a membrane impermeable cargo) in the reply filed on August 19, 2026, is acknowledged. Additionally, Applicant’s election without traverse of Species A (i.e., a non-anionic or charge-neutral polynucleotide analog moiety as a membrane impermeable cargo, the liver as the intracellular biological target, and at least 80% identity to SEQ ID NO: 13 where the cargo and agent are covalently linked at the C-terminus of the agent via a non-cleavable linker ) in the reply filed on August 19, 2026, is acknowledged.
Status of Claims
Claims 1-64 were originally filed on September 28, 2023.
The amendment received on April 26, 2024, canceled claims 1-64; and added new claims 65-84. The amendment received on August 19, 2026, canceled claims 65-83; amended claim 84; and added new claims 85-99.
Claims 84-99 are currently pending and claims 84-87, 89-90, and 92-99 are under consideration as claims 88 and 91 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on August 18, 2026.
Priority
The present application claims status as a 371 (National Stage) of PCT/CA2022/050472 filed March 29, 2022, and claims priority under 119(e) to U.S. Provisional Application No. 63/167,244 filed on March 29, 2021.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on December 20, 2024; December 23, 2025; and August 19, 2026, are being considered by the examiner.
Claim Interpretation
For purposes of applying prior art, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation set forth below, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
For claim 84, the Examiner is interpreting the scope of specific claim language as follows. With respect to a synthetic peptide shuttle agent, it is noted that the instant specification defines a “peptide” as meaning any peptide-linked chain of amino acids, which may or may not comprise any type of modifications (See instant, pg. 3, last paragraph). The peptide modifications that are envisaged includes modifications that do not destroy the cargo transduction activity of the shuttle agents or the biological activity of the cargoes (See instant, pg. 3, last paragraph). The instant specification also defines “synthetic” as referring to non-naturally occurring molecules that can be produced in vitro (See instant, pg. 4, 2nd paragraph). As such, the claimed synthetic peptide shuttle agent encompasses any peptide-linked chain of amino acids, which may or may not comprise any type of modifications that do not destroy the cargo transduction activity of the shuttle agents or the biological activity of the cargoes, and is non-naturally occurring molecules that can be produced in vitro.
Furthermore, the synthetic peptide shuttle agent structurally requires a shuttle agent core motif comprising a core amphipathic alpha-helical motif at least 12 amino acids long having a solvent-exposed surface comprising a discrete positively-charged hydrophilic face and a discrete hydrophobic face. The instant specification defines a “shuttle agent core motif” as referring to a common structural feature shared amongst the majority of synthetic peptide shuttle agents that exhibit robust cargo transduction activities in vitro and/or in vivo – i.e., the presence of an amino acid sequence predicted to adopt an amphipathic alpha-helical motif in aqueous solution of at least 12 to 15 amino acids long having a solvent-exposed surface comprising a discrete positively-charged hydrophilic face and a discrete hydrophobic face (See instant, pg. 17, 2nd paragraph). As such, the scope of claim 84 recites the definition of a shuttle agent core motif. The positively-charged hydrophilic face refers to a region that does not comprise an amino acid with a negatively charged side chain at physiological pH, (e.g., Asp or Glu) (See instant, pg. 17, 2nd paragraph). Although not included in the definition, an ordinary skilled artisan would expect the region representing the positively-charged hydrophilic face to contain at least one positively-charged hydrophilic amino acid, e.g.,. Lys or Arg. Moreover, the instant specification defines “discrete” as referring to a clear physical separation between solvent-exposed regions on the shuttle agent core motif such that there is no or minimal overlap between the cationic amino acid side chains forming the positively-charged hydrophilic face and the hydrophobic side chains of forming the hydrophobic face (See instant, pg. 17, 2nd paragraph). As such, the claimed shuttle agent core motif structurally requires at least 12 amino acid residues where these 12 residues are separated into at least two regions, i.e., a positively-charged hydrophilic face and a hydrophobic face, that do not or minimally overlap such that the positively-charged hydrophilic region contains at least one positively charged residue but does not contain any negatively charged residues. However, there is no structural requirement as to the length of each of these faces. As long as an amino acid sequence contains two separate regions, a positively-charged hydrophilic region and a hydrophobic region, where the sequence is at least 12 amino acids in length, the structural limitations as to what constitutes a shuttle agent core motif is met. Thus, when considered as a whole, the claimed synthetic peptide shuttle structurally requires a non-naturally occurring amino acid sequence of at least 12 amino acid residues where these 12 residues are separated into at least two regions, i.e., a positively-charged hydrophilic face and a hydrophobic face, that do not or minimally overlap such that the positively-charged hydrophilic region contains at least one positively charged residue but does not contain any negatively charged residues, and where the amino aid sequence can be modified in any manner thereby including substitutions, deletions, insertions, and post-translational modifications.
Furthermore, it is noted that as long as the structural limitations are met, the amino acid sequence will form the physical property of an alpha-helix with a solvent-exposed surface comprising the two required regions. Thus, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003). Therefore, as long as the structural limitations are met, the physical properties will inherently be present.
Sequence Interpretation
For claims 96-97, please note that the Examiner is interpreting the scope as open-ended requiring at least 80% identity to elected SEQ ID NO: 13 with any N- and/or C-terminal additions. It is noted that SEQ ID NO: 13 is 34 amino acids in length, and thus, the scope of claims 96-97 encompass up to 6 amino acid modifications including substitutions, deletions and/or insertions.
Drawings
The drawings; in particular, Figures 4-16, are objected to because of the following reason:
The drawings have a line quality that is too light to be reproduced (weight of all lines and letters must be heavy enough to permit adequate reproduction) or text that is illegible (reference characters, sheet numbers, and view numbers must be plain and legible) see 37 CFR 1.84(l) and (p)(1)); See Figure(s) 4-16.
For Figures 4-8, it is noted that the chemical structures are not legible as the line quality is too faint. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities: on page 32, teaches SEQ ID NO: 372 twice but only one of the two sequences includes the sequence identifier. It is respectfully requested that the sequence identifier is included after each recitation of the sequence to comply with MPEP 2422 and 37 CFR 1.821(a).
Appropriate correction is required.
Claim Objections
Claim 85 is objected to because of the following informalities: claim 85 recites, “…wherein at least five of the following parameters are respected:…” It is respectfully requested that “are respected” is reworded; for example, wherein the peptide having an overall length of from 15 to 150 amino acids satisfies at least five of the following parameters:” in order to be grammatically correct. Alternative claim language can be utilized. Appropriate correction is required.
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 84-87, 89-90, and 92-99 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. This is a written description rejection.
With regard to the written description requirement, the attention of the Applicant is directed to The Court of Appeals for the Federal Circuit which held that a “written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials.” University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1405 (1997), quoting Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) (bracketed material in original) [The claims at issue in University of California v. Eli Lilly defined the invention by function of the claimed DNA (encoding insulin)] (the case is referred to herein as “Lilly”).
Additionally, it is noted that written description is legally distinct from enablement: “Although the two concepts are entwined, they are distinct and each is evaluated under separate legal criteria. The written description requirement, a question of fact, ensures that the inventor conveys to others that he or she had possession of the claimed invention; whereas, the enablement requirement, a question of law, ensures that the inventor conveys to others how to make and use the claimed invention.” See 1242 OG 169 (January 30, 2001) citing University of California v. Eli Lilly & Co.
Although directed to DNA compounds, this Eli Lilly holding would be deemed to be applicable to any compound or a generic of compounds; which requires a representative sample of compounds and/or a showing of sufficient identifying characteristics; to demonstrate possession of the compound or generic(s). In this regard, applicant is further referred to University of California v. Eli Lilly & Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997); “Guidelines for Examination of Patent Applications Under the 35 USC 112, first paragraph, ‘Written Description’ Requirement” published in 1242 OG 168-178 (January 30, 2001); and Univ. Of Rochester v G. D. Searle and Co. 249 F. Supp. 2d 216 (W.D.N.Y. 2003) affirmed by the CAFC on February 13, 2004 (03-1304) publication pending.
Additionally, Lilly sets forth a two part test for written description:
A description of a genus of cDNA’s may be achieved by means of a recitation of:
a representative number of cDNA’s, defined by nucleotide sequence, falling within the scope of the genus OR of a recitation of structural features common to the members of the genus.
See Regents of the University of California v. Eli Lilly & Co. 119 F.3d 1559 (Fed. Cir. 1997) at 1569.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
Additionally, Cf. University of Rochester v G.D. Searle & Co., Inc., Monsanto Company, Pharmacia Corporation, and Pfizer Inc., No. 03-1304, 2004 WL 260813 (Fed. Cir., Feb. 13, 2004) held that:
Regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.
In the present instance, the specification discloses only limited examples that are not representative of the claimed genus of a “synthetic peptide shuttle agent”; nor do the claims recite sufficient structural feature(s) which is(are) common to members of the genus sufficient to demonstrate possession of the genus. The instant claims define the “synthetic peptide shuttle agent” having shuttle agent core motif that has an amphipathic alpha-helical motif with a minimum length of 12 amino acids with a discrete positively-charged hydrophilic solvent-exposed surface face and a discrete hydrophobic solvent-exposed surface face with various overly generic “parameters”. The claimed “synthetic peptide shuttle agent” is also defined by functional properties (i.e., deliver the membrane-impermeable cargo to an intracellular biological target; and wherein clauses recited in claims 85-86). While claims 96-97 also refer to elected SEQ ID NO: 13, the 34mer must only have 80% identity to SEQ ID NO: 13. However, as discussed in the “Claim Interpretation” section supra, the amino acid sequence of the synthetic peptide shuttle agent encompasses one or more modifications including residue substitutions, deletions, and/or insertions, but where the scope of claims 96-97 are encompass up to 6 residue modifications. As such, the amino acid sequence of the synthetic peptide shuttle agent of claim 84 encompasses any amino acid sequence that is at least 12 amino acids in length and has a positively-charged hydrophilic region with at least one positively-charged residue and a hydrophobic region where each residue can be modified. Thus, the scope of the claimed synthetic peptide shuttle agent does not require a core structure or sequence necessary for the agent to exhibit the claimed functions. The CAFC held that a functional definition is insufficient to adequately describe a product, therefore, an adequate written description not based on a functional definition is necessary.
The Examiner further notes the present claims stated by Applicant are broader in scope that those that were held to be impermissible in Lilly because, unlike Lilly, Applicants’ claims encompass a vast number of “synthetic peptide shuttle agent” (e.g. the limitations that do not include SEQ ID NO: 13 and the limitations which include vastly different variants of SEQ ID NO: 13). There is not a common core structure/sequence disclosed for the recited activity. The specification is silent with regard to a specific common core structure and/or which amino acids of SEQ ID NO: 13 are critical for the recited function. Therefore, Applicant is using inadequately described “parameters” to inadequately describe the claimed “synthetic peptide shuttle agent”. Consequently, there is no teaching that would allow a person of skill in the art to determine a priori that the Applicant was in possession of the full scope of the claimed invention at the time of filing because there is no common structural attributes that can link together all of the claimed “synthetic peptide shuttle agents”.
While the general knowledge and level of skill in the art for CPP (cell penetrating peptides) is high, this knowledge and level of skill does not supplement the omitted description because specific, not general, guidance is needed for the “synthetic peptide shuttle agent”. Since the disclosure fails to describe the common attributes or characteristics that identify all of the members of the genus or even a substantial portion thereof, and because the genus is vast and highly variant (e.g. refer to the various “parameters”, 80% identity to SEQ ID NO: 13 thereby encompassing up to 6 residue modifications, and variants/fragments per the definition of what constitutes a peptide), the limited examples in the specification (please refer to results in the specification regarding SEQ ID NO: 13 (i.e., FSD10) where the first 15 residues constitute a core region exhibiting over 20% cargo transduction cargo; and SEQ ID NO: 13 is modified with a PEG moiety) are insufficient to teach the entire genus. See Figures 2-4 and 45-46 and Examples 2 and 4-5.
The specification discloses only limited examples that are not representative of the claimed genus of a “synthetic peptide shuttle agent”; nor do the claims recite sufficient structural feature(s) which is(are) common to members of the genus sufficient to demonstrate possession of the genus. Therefore, the teachings in the specification are general teachings relating without guidance as to the individual components of the product. In addition, there are numerous “synthetic peptide shuttle agent” that could be employed in the invention with little direction or guidance for one of skill in the art to practice the claimed invention. The expedient statements in the specification do not relate to an adequate disclosure or how to make and use the claimed invention. Consequently, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to adequately describe the vast genus. Thus, Applicant does not appear to be in possession of the claimed genus.
Please note: it is well-known in the art that differences in length, composition, and/or substitutions can alter CPP function. See Mitchell et al., 2000, Polyarginine enters cells more efficiently than other polycationic homopolymers, J Peptide Res, 56: 318-325.
Claim Rejections - 35 USC § 103
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
Claims 84-87, 89, and 92-99 are rejected under 35 U.S.C. 103 as being unpatentable over Jayaram et al. WO 2020/198151 A1 published October 1, 2020.
For claims 84, 86-87, 89, 92, and 96-97, ‘151 teaches compositions relating to a targeted active gene editing agent (TAGE agent) comprising an extracellular cell membrane-bound molecule, and a site-directed modifying polypeptide that recognizes a nucleic acid sequence where the extracellular cell membrane binding moiety and the site-directed modifying polypeptide are stably associated such that the site-directed modifying polypeptide can be internalized into a cell displaying the extracellular cell membrane-bound molecule (See ‘151, pg. 2, last paragraph to pg. 3, 1st paragraph; pg. 11, last paragraph). ‘151 teaches that the extracellular cell membrane binding moiety can be a cell penetrating peptide that promotes cellular and/or nuclear internalization and an antigen-binding polypeptide (See ‘151, pg. 3, 2nd and 5th paragraph; pg. 11, last paragraph). The site-directed modifying polypeptide and the CPP are covalently conjugated via a linker such as a cleavable or non-cleavable linker (See ‘151, pg. 12, 6th paragraph; pg. 46, 3rd to 4th paragraph; pg. 113, 4th paragraph; pg. 114, 2nd paragraph). Moreover, the site-directed modifying polypeptide contains a conjugation moiety as a linker that allows the protein to be conjugated to a CPP that internalizes within a target cell’s extracellular membrane (See ‘151, pg. 46, 1st paragraph; pg. 109, 1st and 3rd paragraph). The CPP and/or site-specific modifying polypeptide can be modified and/or synthetized to contain a suitable protein linking group at its N-terminus, C-terminus, and/or an amino acid side group for the purpose of crosslinking the CPP to a site-specific modifying polypeptide (See ‘151, pg. 114, 2nd paragraph). As such, ‘151’s TAGE agent contains a CPP covalently conjugated to a cargo where the CPP is covalently conjugated to the cargo via the CPP’s N- or C-terminus and where the cargo is to be delivered to a biological target as recited in instant claim 84; and with respect to where the CPP is covalently conjugated in a non-cleavable fashion to the cargo as recited in instant claim 87.
With respect to the synthetic peptide shuttle agent, as discussed supra, ‘151 teaches that the extracellular cell membrane binding moiety can be a cell penetrating peptide that promotes cellular and/or nuclear internalization and an antigen-binding polypeptide (See ‘151, pg. 3, 2nd and 5th paragraph; pg. 11, last paragraph). The CPP can be characterized as being able to facilitate the movement or traversal of a molecular conjugate across or through one or more of a lipid bilayer, micelle, cell membrane, organelle membrane (e.g., nuclear membrane), vesicle membrane or cell (See ‘151, pg. 109, 5th paragraph). The CPP can be amphiphilic or amphipathic and possess both hydrophilic and lipophilic properties (See ‘151, pg. 110, 3rd paragraph). The CPP can be a CPP listed in Table 1 such as S10 (SEQ ID NO: 32) (See ‘151, pg. 16, 5th paragraph; Table 1). When comparing ‘151’s SEQ ID NO: 32 with instant SEQ ID NO: 13, there is 100% identity. As such, the CPP taught by ‘151 constitutes the instant peptide shuttle agent amino acid sequence as recited in instant claims 96-97.
Furthermore, although ‘151 does not teach that the CPP comprises a shuttle agent core motif comprising a core amphipathic alpha-helical motif and having a solvent-exposed surface comprising a discrete positively-charged hydrophilic face and a discrete hydrophobic face as recited in instant claim 84, since ‘151 teaches a specific species of the instant synthetic peptide shuttle agent (i.e., instant SEQ ID NO: 13), the teachings of ‘151 would necessarily satisfy the genus claim limitations as recited in instant claim 84. Pursuant under MPEP 2131.02(I), a species will anticipate a claim to a genus. "A generic claim cannot be allowed to an applicant if the prior art discloses a species falling within the claimed genus." The species in that case will anticipate the genus. In re Slayter, 276 F.2d 408, 411, 125 USPQ 345, 347 (CCPA 1960); In re Gosteli, 872 F.2d 1008, 10 USPQ2d 1614 (Fed. Cir. 1989). Furthermore, pursuant under MPEP 2131.02(II), when the species is clearly named, the species claim is anticipated no matter how many other species are additionally named. See Ex parte A, 17 USPQ2d 1716 (Bd. Pat. App. & Inter. 1990). Similarly, by teaching that the CPP can be instant SEQ ID NO: 13, the teachings of ‘151 satisfy the limitations and parameters recited in instant claim 86 (note: two adjacent Lys residues; six residues of L, I, F, V, W, and/or M representing 17.6%; 19 residues of A, C, G, I, L, M, F, P, W, Y, and V representing 55.8%; 4 residues of N, Q, S, and T representing 11.7%; 20 residues of A, L, K, or R representing 58.8%; 29% of A and L; 8% of L; 29% of K and R; 0% of D and E; 14 residues of Q, Y, W, P, I, S, G, V, F, E, D, C, M, N, T and H representing 41%; and a difference of 0% when comparing the total percentage of A and L (i.e., 10 aa) and the total percentage of K and R (i.e., 10 aa)).
With respect to the membrane-impermeable cargo, as discussed supra, ‘151 teaches a CPP stably associated with a site-directed modifying polypeptide that recognizes a nucleic acid sequence. ‘151 defines “stably associated” as referring to the ability of the extracellular cell membrane binding moiety (e.g., CPP) and the site-directed modifying polypeptide to complex in such a way that the complex can be internalized into a target cell such that nucleic acid editing can occur within the cell (See ‘151, pg. 37, 3rd paragraph). The site-directed modifying polypeptide comprises a nuclease such as a DNA endonuclease (See ‘151, pg. 4, 2nd paragraph; pg. 11, last paragraph). The TAGE agent further comprises a guide RNA that specifically hybridizes to a target region of the genome of the cell where the guide RNA and the site-directed modifying polypeptide form a ribonucleoprotein (See ‘151, pg. 4, 3rd paragraph; pg. 11, last paragraph). As such, the site-directed modifying polypeptide constitutes recombinant protein or nucleoprotein and a therapeutic cargo as recited in instant claims 89 and 92. Although ‘151 does not expressly teach that the site-directed modifying polypeptide is membrane impermeable, since the site-directed modifying polypeptide can be a DNA endonuclease and/or forms a ribonucleoprotein with a guide RNA thereby constituting a recombinant protein or nucleoprotein, it would necessarily follow that ‘151’s site-directed modifying polypeptide is a species of membrane impermeable cargo. Pursuant under MPEP 2131.02(I), a species will anticipate a claim to a genus. "A generic claim cannot be allowed to an applicant if the prior art discloses a species falling within the claimed genus." The species in that case will anticipate the genus. In re Slayter, 276 F.2d 408, 411, 125 USPQ 345, 347 (CCPA 1960); In re Gosteli, 872 F.2d 1008, 10 USPQ2d 1614 (Fed. Cir. 1989). Furthermore, pursuant under MPEP 2131.02(II), when the species is clearly named, the species claim is anticipated no matter how many other species are additionally named. See Ex parte A, 17 USPQ2d 1716 (Bd. Pat. App. & Inter. 1990).
With respect to where the membrane impermeable cargo that binds or is to be delivered to an intracellular biological target, as discussed supra, ‘151 teaches that the extracellular cell membrane binding moiety and the site-directed modifying polypeptide are stably associated such that the site-directed modifying polypeptide can be internalized into a cell displaying the extracellular cell membrane-bound molecule (See ‘151, pg. 2, last paragraph to pg. 3, 1st paragraph; pg. 11, last paragraph). Moreover, ‘151 teaches that the site-directed modifying polypeptide can be a DNA endonuclease that further comprises a guide RNA thereby forming a ribonucleoprotein. Since the site-directed modifying polypeptide is intended to edit a target cell’s nucleic acid, it would necessarily follow that the cargo is delivered into the intracellular space of the target cell. Thus, the teachings of ‘151 satisfy the intended use recited in instant claim 84.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant specification to follow the teachings of ‘151 and utilize a CPP such as instant SEQ ID NO: 13 as an extracellular cell membrane binding moiety covalently bound to a ribonucleoprotein as a site modifying polypeptide via a non-cleavable linker bound to the N- or C-terminus of the CPP in order to deliver the ribonucleoprotein to an intracellular biological target. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because delivering a cargo such as a ribonucleoprotein intracellularly to a target cell in order to edit the target cell’s nucleic acid was known to be achieved by covalently conjugating a CPP such as instant SEQ ID NO: 13 to the ribonucleoprotein via a cleavable or non-cleavable linker at the N- or C-terminus if the CPP as taught by ‘151. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that the composition comprising an extracellular cell membrane binding moiety conjugated to a site modifying polypeptide of ‘151 was used to deliver the site modifying polypeptide into a target cell, and therefore, utilizing a CPP such as instant SEQ ID NO: 13 as the extracellular cell membrane binding moiety and a ribonucleoprotein as the site modifying polypeptide where the two agents are covalently bound via a non-cleavable linker at the CPP’s N- or C-terminus would support the delivery of the site modifying polypeptide into the intracellular space of a target cell in order to edit the target cell’s nucleic acid by constituting the simple substitution of one known element for another to obtain predictable results and/or some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
For claims 85 and 95, ‘151 does not expressly teach where the shuttle agent is sufficient to increase cytosolic/intracellular transduction of the membrane-impermeable cargo, where the discrete positively-charged hydrophilic face harbors a cluster of positively charged residues on one side of the helix defining a positively charged angle of 40° to 160° in Schiffer-Edmundson helical wheel representation, where the discrete hydrophobic face harbors a cluster of hydrophilic amino acid residues on an opposing side of the helix defining a hydrophobic angle of 140° to 280° in Schiffer-Edmundson helical wheel representation, and where the synthetic peptide shuttle agent has a grand average of hydropathicity (GRAVY) index of less than -0.35. However, as discussed supra, ‘151 teaches instant SEQ ID NO: 13 as a shuttle agent.
MPEP 2112-2112.02 states that when a reference discloses all the limitations of a claim except for a property or function, and the examiner cannot determine whether or not the reference inherently possesses properties which anticipate or render obvious the claimed invention but has basis for shifting the burden of proof to applicant as in In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980). In the instant case, as discussed supra, ‘151 teaches the claimed structural limitations of the shuttle agent.
The Patent and Trademark Office is not equipped to conduct experimentation in order to determine whether or not applicants’ shuttle agent differs, and if so to what extent, from the shuttle agent taught in ‘151. The cited art taken as a whole demonstrates a reasonable probability that the shuttle agent of ‘151 is either identical or sufficiently similar to the claimed shuttle agent that whatever differences exist are not patentably significant. Therefore, with the showing of the reference, the burden of establishing non-obviousness by objective evidence is shifted to the Applicants.
Merely because properties of a shuttle agent are not expressly taught in a reference does not make the known shuttle agent patentable. The shuttle agent possesses properties necessarily present which might not be displayed in the tests used in ‘151. Accordingly, the teachings of ‘151 are a sufficient basis that the shuttle agent of instant SEQ ID NO: 13 is sufficient to increase cytosolic/intracellular transduction of the membrane-impermeable cargo, where the discrete positively-charged hydrophilic face harbors a cluster of positively charged residues on one side of the helix defining a positively charged angle of 40° to 160° in Schiffer-Edmundson helical wheel representation, where the discrete hydrophobic face harbors a cluster of hydrophilic amino acid residues on an opposing side of the helix defining a hydrophobic angle of 140° to 280° in Schiffer-Edmundson helical wheel representation, and where the synthetic peptide shuttle agent has a grand average of hydropathicity (GRAVY) index of less than -0.35.
In the alternative, even if the claimed shuttle agent is not identical to the ‘151 shuttle agent with regard to some unidentified properties, the differences between that which is taught and that which is claimed are considered to be so slight that the ‘151 shuttle agent is likely to inherently possess the same properties of the claimed shuttle agent particularly in view of the similar structural characteristics which they have been shown to share. Thus, the claimed shuttle agent would have been obvious to those of ordinary skill in the art under the meaning of USC 103. Accordingly, the claimed invention as a whole was at least prima facie obvious, especially in the absence of sufficient, clear, and convincing evidence to the contrary.
For claims 93-94, ‘151 teaches that the TAGE agent can be administered transdermally, subcutaneously, intravenously, intramuscularly, intraocularly, intraosseously or intratumorally (See ‘151, pg. 126, 3rd paragraph). Suitable dosage forms include solutions, suspensions, dispersions, or emulsions and can include a sterile diluent such as water for injection (See ‘151, pg. 126, 5th paragraph). As such, ‘151 expressly teaches that the TAGE agent can be a parenteral pharmaceutical composition as recited in instant claim 93.
Although ‘151 does not expressly teach that the TAGE agent can be formulated as an intranasal pharmaceutical composition, the TAGE agent can be in the form of a solution. Pursuant to MPEP 2111.04(I), [c]laim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. However, examples of claim language, although not exhaustive, that may raise a question as to the limiting effect of the language in a claim are:
(A) "adapted to" or "adapted for" clauses;
(B) "wherein" clauses; and
(C) "whereby" clauses.
The court has found that the determination of whether clauses such as “wherein” and “whereby" is a limitation in a claim is dependent on the specific facts of the case. If the “wherein" or “whereby” clause limits a process claim where the clause gives meaning and purpose to the manipulative steps, it should be given patentable weight. Griffin v. Bertina, 285 F.3d 1029, 1034, 62 USPQ2d 1431 (Fed. Cir. 2002). However, the court also found (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” In the instant case, the claimed composition is intended to be formulated as a parenteral or intranasal pharmaceutical composition where the pharmaceutical composition being parenteral or intranasal constitutes the intended use of the composition, and thus, the structure imparted by such a use would be one requiring the composition to be in a form capable of parenteral or intranasal administration. Since ‘151 discloses administering the TAGE agent as a solution, the structural limitation imparted by the “wherein” clauses are met. Therefore, the teachings of ‘151 satisfies the claim limitations as recited in instant claims 93-94.
For claims 98-99, ‘151 teaches where a composition comprising an extracellular cell membrane binding moiety and a site modifying polypeptide was detected in liver tissue (See ‘151, pg. 28, 3rd paragraph). However, ‘151 does not expressly demonstrate transduction of a site modifying polypeptide when the extracellular cell membrane binding moiety is a amphipathic CPP such as SEQ ID NO: 13. As discussed supra, for claim 84, delivering the membrane impermeable cargo to an intracellular biological target constitutes an intended use of the claimed composition. As such, a specific species of intracellular biological target being the liver would further limit the intended use of the claimed composition.
Pursuant to MPEP 2111.04(I), [c]laim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. However, examples of claim language, although not exhaustive, that may raise a question as to the limiting effect of the language in a claim are:
(A) "adapted to" or "adapted for" clauses;
(B) "wherein" clauses; and
(C) "whereby" clauses.
The court has found that the determination of whether clauses such as “wherein” and “whereby" is a limitation in a claim is dependent on the specific facts of the case. If the “wherein" or “whereby” clause limits a process claim where the clause gives meaning and purpose to the manipulative steps, it should be given patentable weight. Griffin v. Bertina, 285 F.3d 1029, 1034, 62 USPQ2d 1431 (Fed. Cir. 2002). However, the court also found (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” In the instant case, the claimed composition is intended to be delivered to an intracellular biological target such as the liver thereby constituting the intended use of the composition. However, since there is no structure imparted by such a use, the teachings of ‘151 satisfy the intended use of the “wherein” clause. Therefore, the teachings of ‘151 satisfies the claim limitation as recited in instant claims 98-99.
Claims 89-90 are rejected under 35 U.S.C. 103 as being unpatentable over Jayaram et al. WO 2020/198151 A1 published October 1, 2020, in view of Genetic Engineering & Biotechnology News, available online at https://www.genengnews.com/news/peptide-nucleic-acids-used-to-edit-genes-cure-mice-of-inherited-blood-disorder/, 6 pages (2016) (hereinafter referred to as the “PNA reference”), alone or as evidenced by, Intavis Peptide Service, “Peptide Nucleic Acids (PNA) – Overview,” available online at https://intavispeptides.com/en/insights/24, 7 pages (2026).
For claims 89-90, as discussed supra, ‘151 teaches a CPP stably associated with a site-directed modifying polypeptide that recognizes a nucleic acid sequence. ‘151 defines “stably associated” as referring to the ability of the extracellular cell membrane binding moiety (e.g., CPP) and the site-directed modifying polypeptide to complex in such a way that the complex can be internalized into a target cell such that nucleic acid editing can occur within the cell (See ‘151, pg. 37, 3rd paragraph). The site-directed modifying polypeptide comprises a nuclease such as a DNA endonuclease (See ‘151, pg. 4, 2nd paragraph; pg. 11, last paragraph; pg. 55, 1st paragraph). The TAGE agent further comprises a guide RNA that specifically hybridizes to a target region of the genome of the cell where the guide RNA and the site-directed modifying polypeptide form a ribonucleoprotein (See ‘151, pg. 4, 3rd paragraph; pg. 11, last paragraph). As such, the site-directed modifying polypeptide constitutes recombinant protein or nucleoprotein.
Furthermore, ‘151 teaches that the TAGE agent can further comprise a guide DNA where a guide DNA binds to the target DNA sequence and recruits the nuclease (i.e., site modifying polypeptide) (See ‘151, pg. 56, 2nd paragraph; pg. 58, 2nd paragraph). The guide nucleic acid comprises two segments, a “polynucleotide-targeting segment” and a “polypeptide-binding segment” (See ‘151, pg. 58, 3rd paragraph). The polynucleotide-targeting segment comprises a nucleotide sequence that is complementary to a specific sequence within a target sequence (See ‘151, pg. 58, 4th paragraph; pg. 59, 2nd paragraph). An example of single-molecule guide nucleic acid can comprise a CRISPER RNA molecule or a CRISPER repeat sequence (See ‘151, pg. 59, last paragraph; pg. 60, 2nd paragraph). ‘151 also teaches that the DNA-targeting RNA comprises modifications of the nucleotide sequence (See ‘151, pg. 63, 2nd paragraph). The modified nucleotides comprise a modification in a ribose group, a phosphate group, a nucleobase, or a combination thereof (See ‘151, pg. 63, 3rd paragraph). Examples of modifications to the ribose group include 2’-O-methyl, 2’-fluoro, 2-deoxy, and 2’-O-(2-methoxyethyl) (See ‘151, pg. 63, 3rd paragraph). Examples of modifications in the phosphate group include a phosphorothioate modification such as a 2’-O-methyl 3’-phosphorothioate nucleotide (See ‘151, pg. 63, 3rd paragraph). As such, the site modifying polypeptide of ‘151’s TAGE agent that constitutes the instant cargo, contains a polynucleotide analog moiety having a modified backbone in the phosphate group and where the cargo can comprise a CRISPER repeat sequence. However, ‘151 does not expressly teach where the guided DNA or RNA is a non-anionic or charge-neutral polynucleotide analog moiety that has one of the backbone modifications recited in claim 90.
The PNA reference teaches that a PNA is part of a gene-editing system (See PNA reference, pg. 1, last paragraph). Peptide nucleic acids (PNAs) are synthetic molecules that combine a protein-like backbone with the nucleobases found in DNA and RNA (See PNA reference, pg. 2, 1st paragraph) thereby constituting where the backbone is an amide backbone. Moreover, as evidenced by Intavis, PNA has a charge-neutral backbone (See Intavis, pg. 2, 1st paragraph) thereby constituting where PNA is a charge-neutral polynucleotide analog moiety. When deployed by researchers based at Carnegie Mellon University and Yale University, PNAs succeeded in correcting mutations responsible for the blood disorder β-thalassemia—and not just in cell cultures, but in live mice (See PNA reference, pg. 2, 1st paragraph). The PNA reference discusses a study that emphasized that unlike the CRISPR gene-editing system, the PNA system did not incorporate any sort of molecular scissors (See PNA reference, pg. 2, 2nd paragraph). Instead, it consisted of a component that opens up double-stranded DNA, donor DNA that binds to faulty DNA in the vicinity, and another component that coaxes the cell’s own DNA-repair machinery to alter targeted genes (See PNA reference, pg. 2, 2nd paragraph). Encouragingly, the PNA system was observed to significantly decrease unwanted, off-target gene mutations (See PNA reference, pg. 2, 2nd paragraph). PNA forms a triplex with the target cell DNA where the PNA-DNA-PNA triple helix that forms when PNA binds to target DNA leaves a displaced DNA strand thereby inducing DNA repair and catalyzing genome editing (See PNA reference, pg. 2, 2nd paragraph). Furthermore, the PNA reference teaches that the researchers in the study, emphasized that their PNA system circumvented a couple of problems seen with CRISPR gene editing (See PNA reference, 4th paragraph). First, the enzymes in the CRISPR system are large and therefore difficult to administer directly to living animals, so scientists typically remove the cells, treat them in the lab, and then put them back into the body (See PNA reference, 4th paragraph). Second, once inside a cell, these enzymes can indiscriminately cut DNA at sites other than the original gene target (See PNA reference, 4th paragraph). In contrast, the PNA system is compact and fits readily within biocompatible nanoparticles for intravenous delivery (See PNA reference, 5th paragraph). Also, the PNA system does not include any of its own cutting components and so may be less prone to errant cutting—and the resulting off-target effects (See PNA reference, 5th paragraph). Thus, the PNA reference suggests utilizing PNA instead of CRISPER in a gene editing system because PNA offers advantages over a CRISPER gene editing system, i.e., compact and fits readily within biocompatible nanoparticles for intravenous delivery, and does not include any of its own cutting components and so may be less prone to errant cutting—and the resulting off-target effects, and where PNA contains amide, charge-neutral backbone.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant specification to modify the teachings of ‘151 and substitute a PNA as a site modifying polypeptide or as a guided DNA component in a composition comprising a CPP such as instant SEQ ID NO: 13 as an extracellular cell membrane binding moiety covalently bound to the PNA or a nuclease-PNA as a site modifying polypeptide via a non-cleavable linker bound to the N- or C-terminus of the CPP in order to deliver the PNA or nuclease-PNA to an intracellular biological target to edit the genome of the target cell. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because PNA was known to have an amide, charge-neutral backbone, and PNA gene editing systems were known to offer advantages such as compact and fits readily within biocompatible nanoparticles for intravenous delivery, and does not include any of its own cutting components and so may be less prone to errant cutting—and the resulting off-target effects, and where PNA contains amide, charge-neutral backbone as taught by the PNA reference. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that the composition comprising an extracellular cell membrane binding moiety conjugated to a site modifying polypeptide such as a nuclease-guided DNA containing a CRISPER repeat sequence where the ribose or phosphate group can be modified of ‘151 was used to deliver the site modifying polypeptide into a target cell to edit the genome of the target cell, and therefore, substituting PNA as the site modifying polypeptide or as the guided DNA bound to the nuclease would support where the two agents are covalently bound via a non-cleavable linker at the CPP’s N- or C-terminus would support the delivery of the site modifying polypeptide into the intracellular space of a target cell in order to edit the target cell’s nucleic acid by constituting the simple substitution of one known element for another to obtain predictable results and/or some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Conclusion
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/THEA D' AMBROSIO/Primary Examiner, Art Unit 1654
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