DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application, Serial No. 17/553,725 was filed on 12/16/2021, claims benefit under 35 U.S.C 119(e) to provisional application Serial Nos. 63/126,991, filed on 12/17/2020 and 63/287,008, filed on 12/07/2021.
Information Disclosure Statement
The information disclosure statement filed 07/28/2022 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Election/Restrictions
Applicant’s election without traverse of Group I and the species SEQ ID NO. 2 (claims 1, 5-8, 10, 12-15, 20, 30, 37, and 44) in the reply filed on 04/09/2025 is acknowledged.
Claims 9, 11, 13, 16, 24 and 47-48 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected groups and species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/09/2025.
Regarding claim 9 and 11, SEQ ID NO: 29 is not the elected species (although claims 1 and 5 recite SEQ ID NO. 29, the claim is not limited to the sequence of SEQ ID NO. 29, but rather to sequences comprising at least one substitution mutation selected from the positions functionally equivalent to those listed in the claim of SEQ ID NO. 29). See the claim language recites a first and second PBP domain comprising at least one amino acid substitution mutation selected from “the positions functionally equivalent to …. of amino acid sequence of SEQ ID NO. 29” As noted above, Applicant’s elected species of invention is SEQ ID NO. 2, the only functionally equivalent substitution mutation therefore appears to be N11. As such, claims 9 and 11 are withdrawn.
Regarding claim 13 and 16, similarly for the reasoning above, claims 13 and 16 are withdrawn as there is no F436 in Applicant elected species SEQ ID NO: 2.
Regarding claim 24, similarly for the reasoning above, claim 24 is withdrawn as there is no G357 in SEQ ID NO: 2.
Status of the Claims
Claims 1, 5-16, 20, 24, 30, 37, 44, and 47-48 are currently pending.
Claims 2-4, 17-19, 21-23, 25-29, 31-36, 38-43, and 45-46 are cancelled.
Claims 9, 11, 13, 16, 24 and 47-48 are withdrawn from further consideration
Thus claims 1, 5-8, 10, 12-15, 20, 30, 37, and 44 are currently under consideration.
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, 5-8, 10, 12, 14-15, 20, 30, 37, and 44 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.
Claim 1 recites a polypeptide, comprising a first mutated PBP domain and a second PBP domain connected to the first, wherein at least one of the first and second PBP domains comprises at least one amino acid substitution mutation selected from the positions functionally equivalent to K10, N11, Q15, T43, T68, T325, K330, D341, Y357, A360, E391, R395, V405, F436, H455, and D490 of the amino acid sequence of SEQ ID NO: 29. Although the recited language appears somewhat structurally limited, the issue is that the number of potential species encompassed by the recited genus, with the claim of “at least one amino acid substitution in at least one PBP” is actually enormous and there is insufficient evidence that what Applicant was in possession of the entire genus as claimed. For example, referring to the recited language, the claims are not limited to mutations in a two PBP domain polypeptide where one of the PBPs domains is SEQ ID NO. 29, rather see the claims require only that one of the domains comprises substitution mutations selected from positions equivalent to SEQ ID NO. 29 (any sequence with mutations considered “equivalent”), the other domain could be any sequence. See as discussed in more detail below under 35 U.S.C. 112(b), it is not readily clear what would and would not be considered a mutation that is functionally equivalent to those indicated associated with SEQ ID NO. 29. There is no indication in the specification that Applicant was in possession of the entire claimed genus.
Claim 5 recites an opioid biosensor comprising a genus of polypeptide, the polypeptide comprising a first mutated PBP domain and a second PBP domain connected to the first, wherein the opioid biosensor is capable of undergoing a detectable conformational change upon binding to an opioid, wherein at least one of the first and second PBP domains comprises at least one amino acid substitution mutation selected from the positions functionally equivalent to K10, N11, Q15, T43, T68, T325, K330, D341, Y357, A360, E391, R395, V405, F436, H455, and D490 of the amino acid sequence of SEQ ID NO: 29. The analyses applied to claim 1 above also apply to claim 5, and in addition, regarding the biosensor that is capable of detectable conformational change there is no evidence of all species of the recited genus of polypeptides used as a biosensor in the specification, and no indication that each species encompassed by the claims that structurally meets the claimed requirements would also be able to achieve the structural conformational changes as claimed. There is no structure-function correlation to convey possession of all structures that achieve the claimed function. The claims are limited functionally in that claim 5 requires that the claimed genus be capable of serving as a biosensor to detect opioids.
Claim 6 further recites the opioid is an opioid specific to a kappa opioid receptor, delta opioid receptor, or mu opioid receptor, thereby further limiting the genus in terms of the type of biosensor (further limits the function in that the sensor must be capable of detecting opioid from one of the claimed classes).
Claim 7 further similarly as with 6, further narrows the claimed opioid detected by the sensor (i.e., also further narrows the functional requirement of the claimed sensor).
Claims 8 and 10 further recite wherein the first PBP comprises an amino acid sequence at least 80% and 90% identical to position 1-75 of a sequence selected from SEQ ID NOs: 2 (1-27) and the second PBP domain comprises an amino acid sequence at least 80% and 90% identical to positions 325-521 of a sequence. These variables further encompasses a large and variable genus without specific, identified changes. These claims further encompass a large and variable genus of polypeptides such as stated in the specification [0064] “In the case of a polypeptide, a variant can have deletions, substitutions, additions of one or more amino acids in comparison to the reference polypeptide”. As discussed above, the claims are directed to a large genus and one having ordinary skill cannot readily visualize what structures that meet the structural requirements of the claim, also exhibit the required claimed functional ability. There is insufficient support in the originally filed specification for the entire genus as claimed (which encompasses any variants having 80% identity).
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. See MPEP 2163.
However, for example, none of the claims above recite a structure that correlates with the function (for example, with respect to claims 5, 8 and 10) such to allow one having ordinary skill to envision which particular species are encompassed by this extremely large and variable genus of polypeptides. In other words, none of the claims require a specific structure/sequence that would create a periplasmic binding protein (PBP) domain that would be capable of undergoing conformational change upon binding to an opioid. Regarding claims 8 and 10, the claims contain some structural information, namely that at least the first PBP “comprises an amino acid sequence at least 80% identical to position 1-75 (and 325-521)” [of a sequence], but this structural information alone is not enough for one of ordinary skill in the art to predict function of each variant.
Regarding Applicant’s actual reduction to practice, based on the originally filed specification, specific species that meet both the structure and function required of the claimed invention are described, but they include only the specific PBPs of Tables 1 (non-elected sequences) and 2 (specific substitution mutations for an unelected sequence), and table 3 (exemplary opioid biosensors and their preferred opioid ligand) starting at pages 17, 25, and 27 respectively. Further, there are no disclosed 80-90% identity variants of the SEQ IDs provided as species in the specification, outside of those previously referenced, which perform/achieve the recited function (no exemplary species of any variants as claimed, at 80-90% identity, referring to claims 8 and 10). Each possible mutation within the large and variable genus as claimed could potentially change the structure and function of the polypeptide. For example, as evidence that even a single substitution is capable of producing functional change can be found in Sakaguchi et al ( Engineering of ligand specificity of periplasmic binding protein for glucose sensing, abstract, 2008):
“A novel glucose-sensing molecule was created based on galactose/glucose-binding protein (GGBP(a PBP which has a high affinity for both d-galactose and d-glucose, Introduction, 3rd paragraph)). GGBP mutants at Asp14, a residue interacting with the 4th hydroxyl group of the sugar molecule, were constructed by mutagenesis to improve the ligand specificity of GGBP. The autofluorescence-based analysis of the binding abilities of these engineered GGBPs showed that the GGBP mutants Asp14Asn and Asp14Glu bound only to glucose in a concentration-dependent manner, without being affected by the presence of galactose”.
In a large genus of polypeptides, changes in amino acids can lead to potential changes in structure and function of the polypeptides. In addition, the 521 amino acid polypeptide of SEQ ID NO: 2 (Applicant’s elected species) would have the potential for an extremely broad genus because polypeptides that meet 80% identity will have 5.5543154639e+111 possible permutations, and polypeptides that meet 90% identity will have 1.6797857508e+72 possible permutations. Because of the numerous structural possibilities encompassed by the claims (as discussed above), the breadth of the recited polypeptides in the claims is much broader in scope than what is supported by Applicant’s originally filed specification.
Although Applicant appears to be in possession of the specific biosensors recited in the specification in tables 1-3, these species do not extend to convey possession of any and all possible species encompassed by the extremely broad and variable genus, including possible variants as claimed by polypeptides having 80 and 90% identity to portions of sequences as recited in the claims (see for example, claim 8 for example “at least 80% identity” with particular stretches of residues within larger claimed sequences). The large number of possible permutations contained in these identities are not readily supported by the description of the invention, and there is no evidence that all structures encompassed by the claims would still retain the recited functional ability as required of the biosensor claims.
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. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014).
Thus, when there is substantial variation within the genus, as here in which each of the two separate PBP domains can have unspecified sequences (either from an unspecified mutation to a given AA or by 80-90% identity of the polypeptide), it would be necessary that the disclosed species convey some structure-function correlation such that one having ordinary skill, could visualize what species encompassed by the genus would be capable of the recited functional ability. However, one of ordinary skill in the relevant art cannot envision the structure of any other polypeptides with the required function, the specification only provides the binding partners of the recited biosensors with specific mutations and corresponding function. Without some structure-function correlation, it is not possible to visualize, not only what species are encompassed by the claimed genus that retain the required function, but even further it is not possible to then visualize of those species, what variants would also be capable of the required function.
Since only specific species of binding polypeptides are described in the specification as falling within the recited genus above (meeting both the structural and functional requirement), the claims above which claim 80-90% variation in the sequences are also not sufficiently described in order to satisfy the written description requirement. A representative number of species that would allow one to correlate structure and function has not been provided to describe such a massive genus, the permutations of which are referred to above. Each biosensor described in the specification is specific to one opioid, as shown in figures 2-28. One of ordinary skill in the art from the disclosed representative number of species cannot readily visualize what other species having the claimed structure also exhibit the required/claimed function (in terms of all of the permutations (species) in said genus including 80-90% variations).
Owed to the variation among the polypeptides of the genus as broadly as currently claimed, there is inadequate representation of the functionally defined polypeptide genus. For example, see the following as evidence of unpredictability. Burgess (Journal of Cell Biology, 1990) teaches in the abstract replacement of a single “lysine” residue at position 118 of acidic fibroblast growth factor by “glutamic acid” led to the substantial loss of heparin binding, receptor binding and biological activity of the protein (Burgess et al., J of Cell Bio. 111:2129-2138, 1990). Lazar et al (Molecular and Cellular Biology, 1988) teach in the abstract that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen (Lazar et al. Molecular and Cellular Biology 8:1247-1252, 1988). As these references illustrate, it is unpredictable that a polypeptide variant of a known target protein binder will also bind said target, rather even seemingly small substitutions can change binding.
Thus, while applicant has described some species within the genus recited, the genus is very large and would encompass peptide structures that cannot be visualized such to know what is and is not encompassed by the recited claims. One of ordinary skill in this art cannot determine the polypeptide structures encompassed by the claimed/recited genus with 80-90% variation defined by function given the breadth of possible permutations claimed. For example, the scope of the claimed could also encompass polypeptides not even made yet (since the genus is described only in terms of function and some unspecified structure in relation substitutions in SEQ ID NO. 29). Thus, the described species cannot be considered representative of the entire recited genus of peptides.
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, 5, 15 and 20 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.
Claims 1 and 5 are indefinite because they refers to PBP domain sequences in terms of their functional equivalence to a sequence that is not the claimed sequences, see specifically the claim recites “first and second PBP domain comprises at least one amino acid substitution mutation selected from the positions functionally equivalent to… of amino acid sequence of SEQ ID NO: 29”. In the specification, paragraph [0062] it is stated “A functionally equivalent residue of an amino acid used herein typically can refer to other amino acid residues having physiochemical and stereochemical characteristics substantially similar to the original amino acid. The physiochemical properties include water solubility (hydrophobicity or hydrophilicity), dielectric and electrochemical properties, physiological pH, partial charge of side chains (positive, negative or neutral) and other properties identifiable to a person skilled in the art. The stereochemical characteristics include spatial and conformational arrangement of the amino acids and their chirality. For example, glutamic acid is considered to be a functionally equivalent residue to aspartic acid in the sense of the current disclosure. Arginine and lysine are considered as functionally equivalent residues to histidine”.
Outside of the specific examples given in the specification, one of ordinary skill in the art would not be able to readily visualize other substitutions which would be equivalent. For example, [0010] recites an amino acid substitution of N11V, but these residues differ in side chains and polarity making them not functionally equivalent according to the definition in the specification recited above. This substitution, and others which replace residues with ones having different properties, makes one of ordinary skill in the art unable to visualize what substitutions, would make a mutation functionally equivalent. There is no disclosure of what substitutions would result in a structurally and functionally equivalent polypeptide.
Claim 15 recites “substitution mutation of N11V or a substitution mutation homologous to N11V”. It is unclear what is meant by homologous. The specification defines homologous as substantially identical in paragraph [0063]. It is not readily clear what mutations would be substantially identical to N11V other than N11V itself and there is no indication in the originally filed specification as to what substituted mutations would be considered as “substantially homologous” to N11V.
Claim 20 recites “substitution mutation of N11E or a substitution mutation homologous to N11E”. It is unclear what is meant by homologous. The specification defines homologous as substantially identical in paragraph [0063]. It is not readily clear what mutations would be substantially identical to N11E other than N11E itself and there is no indication in the originally filed specification as to what substituted mutations would be considered as “substantially homologous” to N11E.
Closest Prior art
The following is a statement of reasons for the indication of allowable subject matter:
Regarding claims 1 and 5, the closest prior art of record is Marvin et al (US20190376964), and Marvin et al (11162942). Both teach a SEQ ID NO: 185 and SEQ ID NO:186, each with a 94% identity to the instant SEQ ID NO: 2, as a polypeptide used as a biosensor with two periplasmic binding domains meant to specifically bind an analyte. Neither of these sequences contain substitutions which are functionally equivalent to those listed in claims 1 and 5. Amino acid positions K10, N11, Q15, T43, T68, T325, K330, D341, Y357, A360, E391, R395, V405, F436, H455, and D490 of the amino acid sequence of SEQ ID NO: 29 are all substituted in the reference SEQ IDs, with the exception of K330 in SEQ ID NO: 185, but none of these substitutions are functionally equivalent as defined in the specification of the application at [0062] where functionally equivalent is defined as “A functionally equivalent residue of an amino acid used herein typically can refer to other amino acid residues having physiochemical and stereochemical characteristics substantially similar to the original amino acid. The physiochemical properties include water solubility (hydrophobicity or hydrophilicity), dielectric and electrochemical properties, physiological pH, partial charge of side chains (positive, negative or neutral) and other properties identifiable to a person skilled in the art. The stereochemical characteristics include spatial and conformational arrangement of the amino acids and their chirality. For example, glutamic acid is considered to be a functionally equivalent residue to aspartic acid in the sense of the current disclosure. Arginine and lysine are considered as functionally equivalent residues to histidine”.
Therefore the independent claims 1 and 5 are free of the prior art, and all claims that depend from claims 1 and 5 are thus free of the art.
Conclusion
No claims are allowed at this time.
As allowable subject matter has been indicated, applicant's reply must either comply with all formal requirements or specifically traverse each requirement not complied with. See 37 CFR 1.111(b) and MPEP § 707.07(a).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JIM ATWELL, D.Sc., M.S., MLS whose telephone number is (571)272-0890. The examiner can normally be reached Generally Mon-Thurs: 7:30-5:00 EST and every other Fri: 7:30-4:00 EST.
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/JIM ATWELL/Examiner, Art Unit 1677
/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677
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