DETAILED ACTION
Status of the Application
Claims 1-18 are pending.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s election of Group I, claims 1-9, drawn to a lipoprotein, as submitted in a communication filed on 2/17/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse.
Claims 10-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 2/17/2026.
Claims 1-9 are at issue and are being examined herein.
Specification
The first paragraph of the specification is objected to because it does not provide the current status of related applications (e.g., now US Patent No. X). Appropriate correction is required.
The specification is objected to for the following reasons. According to page 17, paragraph [0045] of the specification, the N-terminus of SEQ ID NO: 2 comprises the sequence GLYASKLFSNL. However, the sequence listing shows that SEQ ID NO: 2 does not comprise this sequence. Therefore, SEQ ID NO: 2 as disclosed in the specification is not the same as SEQ ID NO: 2 as provided in the sequence listing. Appropriate correction is required.
The specification is objected for not complying with sequence rules. Page 18, paragraph [0050] recites the amino acid sequence “GARASVLS” without the corresponding sequence identifier. Applicant is required to insert the corresponding sequence identifier next to the sequence. See particularly 37 CFR 1.821(d). Appropriate correction is required.
Priority
Acknowledgment is made of a claim for domestic priority under 35 U.S.C. 119(e) to provisional application No. 63/115,696 filed on 11/19/2020.
Acknowledgment is made of a claim for domestic priority under 35 U.S.C. 120 or 121 to US application No. 17/529,860 filed on 11/18/2021.
Drawings
The drawings submitted on 8/02/2024 have been reviewed and are accepted by the Examiner for examination purposes.
Claim Objections
Claims 3 and 9 are objected to due to the recitation of “peptide-polymer”. To be consistent with the language of claim 1, from which these claims depend, the term should be amended to recite “peptide polymer” (no hyphen). Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA )
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 5-6 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claim 5 is indefinite in the recitation of “…lipoprotein of claim 3, wherein the fatty acid is an analogue of myristic acid” for the following reasons. Claim 3 requires the fatty acid to be 12-azidododecanoic acid due to its dependency on claim 2. Claim 5, which ultimately depends from claim 2 requires the fatty acid to be an analogue of myristic acid. Therefore, the scope of claim 5 is broader than the scope of claim 3, thus not being further limiting. For examination purposes, it will be assumed that claim 5 is directed to a lipoprotein that comprises SEQ ID NO: 2 and an analogue of myristic acid which is a fatty acid having the formula R-COOH, wherein R is a linear chain of no more than 15 atoms. Correction is required.
Claim 6 is indefinite in the recitation of “…lipoprotein of claim 3, wherein the fatty acid is 12-azidododecanoic acid” for the following reasons. Claim 3 requires the fatty acid to be 12-azidododecanoic acid due to its dependency on claim 2. Therefore, it is unclear as to how claim 6 further limit claim 3 if the fatty acid required in claim 3 is 12-azidododecanoic acid. For examination purposes, claim 6 will be interpreted as a duplicate of claim 3. Correction is required.
When amending the claims, applicant is advised to carefully review all examined claims and make the necessary changes to ensure proper antecedent basis and dependency.
Claim Rejections - 35 USC § 112(a) or First Paragraph (pre-AIA )
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 5, 7-9 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
As stated in MPEP 2111.01, during examination, the claims must be interpreted as broadly as their terms reasonably allow. Claims 1-2, 5, 7-9 are directed in part to a genus of lipoproteins having any structure or the amino acid sequence of SEQ ID NO: 2, wherein said lipoproteins comprise an intrinsically disordered peptide polymer, wherein said lipoproteins have a genus of non-naturally occurring fatty acids having the formula R-COOH, wherein R is a linear chain of 15 atoms or less, including 12-azidododecanoic acid, wherein said fatty acids are analogues of myristic acid that are substrates of any N-myristoyl transferase. See Claim Rejections under 35 USC § 112(b) or Second Paragraph (pre-AIA ) for claim interpretation.
In University of California v. Eli Lilly & Co., 43 USPQ2d 1938, the Court of Appeals for the Federal Circuit has 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”. As indicated in MPEP § 2163, 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, reduction to drawings, 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 that Applicant was in possession of the claimed genus. In addition, MPEP § 2163 states that a representative number of species means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
There is no actual structural limitation with regard to the members of the genus of lipoproteins comprising non-naturally occurring fatty acids having the recited formula which are substrates of any N-myristoyl transferase required by the claims. While the specification discloses a single protein that comprises an intrinsically disordered peptide polymer (SEQ ID NO: 2) to which a single non-naturally occurring analogue of myristic acid (12-azidododecanoic acid) was linked using a single N-myristoyl transferase (UniProtKB P14743), it provides no clue as to the structural elements required in any protein having an intrinsically disordered peptide polymer that could be a substrate for any N-myristoyl transferase, or the structural elements required in any N-myristoyl transferase that could be used to fuse any fatty acid having the recited formula to any protein as recited. There is no disclosure as to the whether any fatty acid having the recited formula could be attached enzymatically with the only N-myristoyl transferase disclosed to any protein having an intrinsically disordered peptide polymer. No disclosure of a structure/function correlation has been provided which would allow one of skill in the art to recognize which proteins having an intrinsically disordered peptide polymer can be substrates of any N-myristoyl transferase that can catalyze the attachment of any fatty acid having the recited formula to said proteins. No disclosure of a structure/function correlation has been provided which would allow one of skill in the art to recognize which N-myristoyl transferases can be used to attach any fatty acid having the recited formula to any protein as required by the claims.
The claims require a large genus of structurally unrelated proteins that can be substrates of any N-myristoyl transferase that can be used to attach any non-natural fatty acid having the recited formula. The claims also require a genus of fatty acids which is substantially unrelated since the linear chain can have any type of atoms and moieties. A sufficient written description of a genus of polypeptides/fatty acids may be achieved by a recitation of a representative number of fatty acids and a recitation of a representative number of polypeptides defined by their amino acid sequences, or a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus. However, in the instant case, there is no structural feature which is representative of all the members of the genus of polypeptide substrates and enzymes that can be used to attach any of the recited non-natural fatty acids to such substrates, or additional structural features associated with the fatty acids recited so that they can be attached to any protein as recited with the only N-myristoyl transferase provided. Furthermore, while one could argue that the few species disclosed are representative of the structure of all the members of the genus of proteins, fatty acids and enzymes required by the claims, it is noted that the art teaches that (i) protein substrates of N-myristoyl transferases require a particular structural feature for such N-myristoyl transferases to attach a particular fatty acid, and (ii) several examples of how even highly structurally homologous polypeptides can have different enzymatic activities and/or substrate specificities. For example, Witkowski et al. (Biochemistry 38:11643-11650, 1999) teach that one conservative amino acid substitution transforms a β-ketoacyl synthase into a malonyl decarboxylase and completely eliminates β-ketoacyl synthase activity. Tang et al. (Phil Trans R Soc B 368:20120318, 1-10, 2013) teach that two Dehalobacter reductive dehalogenases, CfrA and DcrA, having 95.2% sequence identity to teach other have exclusively different substrates (Abstract; page 7, left column, Discussion, CfrA and DcrA). Seffernick et al. (J. Bacteriol. 183(8):2405-2410, 2001) teach that two naturally occurring Pseudomonas enzymes having 98% amino acid sequence identity catalyze two different reactions: deamination and dehalogenation, therefore having different function. Therefore, since minor structural differences may result in changes affecting function, and no additional information correlating structure with the desired functional characteristics has been provided, one cannot reasonably conclude that the few species disclosed are representative of the structure of all the proteins, enzymes and fatty acids required by the claims.
Due to the fact that the specification only discloses a limited number of species of the genus of enzymes, substrates and non-natural fatty acids, and the lack of description of any additional species by any relevant, identifying characteristics or properties, one of skill in the art would not recognize from the disclosure that Applicant was in possession of the claimed invention.
Claims 1-2, 5, 7-9 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 lipoprotein that comprises SEQ ID NO: 2 which is fused to 12-azidododecanoic acid, does not reasonably provide enablement for lipoproteins having any structure or the amino acid sequence of SEQ ID NO: 2, wherein said lipoproteins comprise an intrinsically disordered peptide polymer, wherein said lipoproteins have non-naturally occurring fatty acids having the formula R-COOH, wherein R is a linear chain of 15 atoms or less, including 12-azidododecanoic acid, wherein said fatty acids are analogues of myristic acid that are substrates of any N-myristoyl transferase. 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 and/or use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2nd 1400 (Fed. Cir. 1988)) as follows: 1) quantity of experimentation necessary, 2) the amount of direction or guidance presented, 3) the presence and absence of working examples, 4) the nature of the invention, 5) the state of prior art, 6) the relative skill of those in the art, 7) the predictability or unpredictability of the art, and 8) the breadth of the claims. The factors which have led the Examiner to conclude that the specification fails to teach how to make and/or use the claimed invention without undue experimentation, are addressed in detail below.
The breadth of the claims. Claims 1-2, 5, 7-9 broadly encompass lipoproteins having any structure or the amino acid sequence of SEQ ID NO: 2, wherein said lipoproteins comprise an intrinsically disordered peptide polymer, wherein said lipoproteins have non-naturally occurring fatty acids having the formula R-COOH, wherein R is a linear chain of 15 atoms or less, including 12-azidododecanoic acid, wherein said fatty acids are analogues of myristic acid that are substrates of any N-myristoyl transferase. See Claim Rejections under 35 USC § 112(b) or Second Paragraph (pre-AIA ) for claim interpretation
The enablement provided is not commensurate in scope with the claims due to the lack of information regarding the structural elements required in any protein having an intrinsically disordered peptide polymer required by the claims that can be a substrate of any N-myristoyl transferase that can catalyze the attachment of any non-natural fatty acid having the recited formula, the lack of information regarding the structural elements required in any N-myristoyl transferase that can catalyze the attachment of any non-natural fatty acid having the recited formula, and the lack of information regarding the fatty acids encompassed by the claims that can be attached to a protein as recited in the claims by the only N-myristoyl transferase disclosed. In the instant case, the specification enables a lipoprotein that comprises SEQ ID NO: 2 which is fused to 12-azidododecanoic acid.
The amount of direction or guidance presented and the existence of working examples. The specification discloses the synthesis of a lipoprotein that comprises SEQ ID NO: 2 which is fused to 12-azidododecanoic acid by a reaction catalyzed by the S. cerevisiae N-myristoyl transferase having the amino acid sequence disclosed in UniProtKB P14743 as a working example. However, the specification fails to provide any clue as to the structural elements required in (i) any protein having an intrinsically disordered peptide polymer required by the claims that can be a substrate of any N-myristoyl transferase that can catalyze the attachment of any non-natural fatty acid having the recited formula, (ii) any N-myristoyl transferase that can be used to attach any non-natural fatty acid having the recited formula, or (iii) the structural elements required in a non-natural fatty acid as recited which can be used by the only N-myristoyl transferase disclosed. There is no disclosure of a structure/function correlation that would allow one of skill in the art to envision the structure of (a) any protein that can be a substrate of any N-myristoyl transferase that can catalyze the attachment of any non-natural fatty acid having the recited formula, (b) any protein that has N-myristoyl transferase activity that can catalyze the attachment of any non-natural fatty acid having the recited formula, or (c) non-natural fatty acids which have the recited formula which are substrates of the S. cerevisiae N-myristoyl transferase disclosed.
The state of prior art, the relative skill of those in the art, and the predictability or unpredictability of the art. The amino acid sequence of a polypeptide determines its structural and functional properties. While the art discloses a limited number of proteins with intrinsically disordered peptide polymers, a limited number of fatty acids which are substrates of N-myristoyl transferases, and a limited number of N-myristoyl transferases, neither the specification nor the art provides a correlation between structure and function such that one of skill in the art can envision the structure of any protein with intrinsically disordered peptide polymers that can be a substrate for any N-myristoyl transferase that can catalyze the attachment of any non-natural fatty acid having the recited formula, a correlation between structure and function such that one of skill in the art can envision the structure of any N-myristoyl transferase that can catalyze the attachment of any non-natural fatty acid having the recited formula, or a correlation between structure and function such that one of skill in the art can envision the structure of a non-natural fatty acid that can be used as a substrate for the S. cerevisiae N-myristoyl transferase having the amino acid sequence disclosed in UniProtKB P14743 disclosed in the specification.
While the argument can be made that the structure/identity of those enzymes and their corresponding polypeptide substrates can be found by structural homology, the art clearly teaches that (i) there is a high level of unpredictability associated with accurate functional annotation of proteins based solely on structural homology, and (ii) modification of a protein’s amino acid sequence to obtain the desired activity without any guidance/knowledge as to which amino acids in a protein are tolerant of modification and which ones are conserved is highly unpredictable. For example, Singh et al. (Current Protein and Peptide Science 19(1):5-15, 2018) disclose different protein engineering approaches and state that despite the availability of an ever-growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility and conformational changes (page 11, left column, last paragraph). Sadowski et al. (Current Opinion in Structural Biology 19:357-362, 2009) teach that much of the problem in assigning function from structure comes from functional convergence, where although a stable structure is required to perform many functions it is not always necessary to adopt a particular structure to carry out a particular function (page 357, right column, first full paragraph). Sadowski et al. further explain that the unexpected and significant difficulties of predicting function from structure show that the potential of structural models for providing novel functional annotations has not yet fully realized. Sadowski et al. also states that while a few successes have been achieved which required manual intervention, the ability to vary the requirements for specificity in prediction means that it is difficult to determine how useful the end result may be for the user (page 361, left column, first full paragraph). The teachings of Singh et al. and Sadowski et al. are further supported by the teachings of Witkowski et al., Tang et al. and Seffernick et al. already discussed above, where it is shown that even small amino acid changes result in unpredictable enzymatic activity changes.
The quantity of experimentation required to practice the claimed invention based on the teachings of the specification. While methods of generating or isolating variants of a polypeptide and enzymatic assays were known in the art at the time of the invention, it was not routine in the art to screen by a trial and error process for an essentially infinite number of enzymes, proteins having intrinsically disordered peptide polymers, and non-natural fatty acids to find (a) N-myristoyl transferases having specificity for fatty acids having the recited formula, (b) fatty acids having the recited formula that can be substrates of N-myristoyl transferases, and (c) proteins having intrinsically disordered peptide polymers that can be substrates of N-myristoyl transferases having specificity for fatty acids having the recited formula. In the absence of (i) a rational and predictable scheme for selecting those proteins having intrinsically disordered peptide polymers, N-myristoyl transferases, and fatty acids most likely to be functional together to form the desired lipoprotein, and/or (ii) a correlation between structure and activity, one of skill in the art would have to test an essentially infinite number of proteins, fatty acids and enzymes to obtain the desired lipoproteins.
Therefore, taking into consideration the extremely broad scope of the claim, the lack of guidance, the amount of information provided, the lack of knowledge about a correlation between structure and the desired function, and the high degree of unpredictability of the prior art in regard to structural changes and their effect on function, one of ordinary skill in the art would have to go through the burden of undue experimentation in order to practice the claimed invention. Thus, Applicant has not provided sufficient guidance to enable one of ordinary skill in the art to make and use the invention in a manner reasonably correlated with the scope of the claims.
Claim Rejections - 35 USC § 102 (AIA )
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-2, 8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kulkarni et al. (Bioconjugate Chemistry 26:2153-2160, 2015) as evidenced by Dunker et al. (J. Mol. Graphics Modell. 19(1):26-59, 2001), and IDEAL (Intrinsically Disordered proteins with Extensive Annotations and Literature) database entry IID50080 (D. melanogaster calmodulin, 2011).
Claims 1-2 and 8 are directed in part to a non-naturally occurring lipoprotein that comprises an intrinsically disordered peptide polymer, wherein said lipoprotein is fused to 12-azidododecanoic acid (ADA), wherein said non-naturally occurring lipoprotein comprises a non-canonical post translational modification.
Kulkarni et al. teach fusion proteins comprising D. melanogaster calmodulin (CAM; page 2158, left column, Cloning, Protein Expression, and Protein Labeling) and recognition peptides from human calcineurin B subunit (RS1) or yeast ADP ribosylation factor (RS2), wherein some of these fusion proteins further comprise a linker peptide SRLIGSA or a hexahistidine linker (page 2154, Figure 1), wherein said fusion proteins were expressed in E. coli that also expressed human NMT1 (N-myristoyl transferase) so that these fusion proteins could be post-translationally modified by the attachment of 12-azidododecanoic acid (non-canonical post translational modification; page 2154, right column, Results and Discussion; page 2153. Abstract). As evidenced by Dunker et al., calmodulin comprises two disorder features (page 37, right column, first two paragraphs, Table 2). Also, as evidenced by IDEAL entry IID50080, D. melanogaster calmodulin comprises disordered peptides (see arrows). Therefore, the non-naturally occurring fusion proteins comprising ADA of Kulkarni et al. anticipate the instant claims as written/interpreted.
Claims 1-2, 7-8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Thinon et al. (Nature Communications 5:4919, pages 1-13, 2014) as evidenced by IDEAL (Intrinsically Disordered proteins with Extensive Annotations and Literature) database entry IID00708 (Proto-oncogene tyrosine-protein kinase Src, 2011) and UniprotKB accession No. P12931 (9/18/2019)
Claims 1-2, 7-8 are directed in part to a non-naturally occurring lipoprotein that comprises an intrinsically disordered peptide polymer, wherein said lipoprotein is fused to 12-azidododecanoic acid (ADA), wherein said non-naturally occurring lipoprotein comprises a non-canonical post translational modification and a canonical post translational modification.
Thinon et al. teach the incorporation of tetradic-13-ynoic (YnMyr) which is an analogue of myristic acid that has the formula recited in claim 1 (Figure 1b, left side, YnMyr formula) to proteins produced by HeLa cells (page 2, Results, The targets of myristate analogue YnMyr in human cells). Thinon et al. teach that YnMyr is a substrate of NMT1 and NMT2 (N-myristoyl transferase, page 2, right column, first paragraph). The incorporation of YnMyr et al. to these proteins is a non-canonical post translational modification. Thinon et al. teach that one of the proteins tagged with YnMyr is c-Src tyrosine kinase (Figure 2d; Supplemental Data 3, Proto-oncogene tyrosine protein kinase Src, P12931). As evidenced by IDEAL entry IID00708, c-Src tyrosine kinase (UniprotKB P12931) has intrinsically disordered regions (see arrows). According to UniprotKB P12931, c-Src tyrosine kinase has several canonical post-translational modifications, such as removal of initiator methionine, dephosphorylation and phosphorylation of tyrosine residues, and ubiquination (see arrows). Therefore, the c-Src tyrosine kinase having YnMyr of Thinon et al. is a non-naturally occurring lipoprotein that has a non-natural fatty acid having the formula recited in claim 1, wherein said non-natural fatty acid is an analogue of myristic acid and a substrate of N-myristoyl transferase, has a canonical post translational modification and a non-canonical post translational modification. As such, the teachings of Thinon et al. anticipate the instant claims as written/interpreted.
Conclusion
No claim is in condition for allowance.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to DELIA M RAMIREZ, Ph.D., whose telephone number is (571) 272-0938. The examiner can normally be reached on Monday-Friday from 8:30 AM to 5:00 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert B. Mondesi, can be reached at (408) 918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
/DELIA M RAMIREZ/Primary Examiner, Art Unit 1652
DR
March 20, 2026