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 .
Detail Action
Claims 1-11 submitted on 7/17/2026 are pending for examination.
Applicants’ election on 7/17/2026 with traverse of group I (claims 1-2, 5-11) directed to a preparation method for a polypeptide, wherein the preparation method comprises the following steps: constructing an engineering strain for fusion-expressing a polypeptide gene with a Sumo tag, and inducing the engineering strain to soluble-express the polypeptide; obtaining a fusion protein containing a polypeptide precursor from the engineering strain by purification; cleaving the fusion protein containing the polypeptide precursor by using a Ulp 1 protease to remove the Sumo tag; purifying a cleavage product of the Ulp 1 protease by a method of acetonitrile combined with heating precipitation or a method of hexafluoroisopropanol precipitation, to obtain the polypeptide, in their response against the restriction requirement of 5/22/2026 is acknowledged. Traversal on the ground that group I and group II claim comprise high degree of unity is considered but found unpersuasive because claims of group I is directed method of use of ULp1 polypeptide, wherein on the other hand group II claims directed predation of ULp1 polypeptide, AS discus in the restriction, If claim 1 is allowed than Group II claims will be rejoined. Claims 3-4 comprise non elected subjects are withdrawn. Claims 1-2, 5-11 are for examination. Election made final.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/4/ 23, 12/2/2024 4/21/2025 and 11/18/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the examiner has considered the IDS statement.
Claim Rejections: 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim claims 1-2, 5-11 (depends on claim 1) is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention
Claim 1 is indefinite in reciting “fusion-expressing a polypeptide gene” make the claims unclear because of following reason:
The term fusion-expressing a polypeptide gene makes the claim unclear what is fusion-expressing? And It is unclear what is polypeptide gene.
Correction required.
Claim 1 is indefinite in reciting “soluble-express the polypeptide” make the claims unclear because of following reason:
The term soluble-express the polypeptide makes the claim unclear as soluble-express the polypeptide make no sense.
Claim 1 is indefinite in reciting “method of acetonitrile” make the claims unclear because of following reason:
An acetonitrile is chemical compound is some time use a polar solvent in chemical reaction. It itself cannot be a method. Makes no sense
Correction required.
Claim 1 is indefinite in reciting “heating precipitation” make the claims unclear because of following reason:
What is heating precipitation? Is it precipitation the polypeptide product by heating clarity required.
Claim 5 is indefinite in reciting “adjusting pH of the cleavage product of the Ulp 1 protease to 5.6” Because how can pH of a product be adjusted is not clear. PH can be adjusted of solution containing the product.
clarity required.
Claim 6 is indefinite in reciting “acetonitrile is acetonitrile aqueous solution” make the claims unclear because of following reason:
An acetonitrile is chemical compound is some time use a polar solvent in chemical reaction. It itself cannot be acetonitrile aqueous solution. Makes no sense
Correction required.
Claim 7 is indefinite in reciting “filtration with membrane of the engineering strain” make the claims unclear because of following reason:
It is unclear what is filtration with membrane of the engineering strain. Makes no sense
Correction required.
Claim 7 is indefinite in reciting “an anion column” make the claims unclear because of following reason:
What is anion column. Anion can not exit it self.Correction required.
Claim 8 is indefinite in reciting “adjusting pH of the cleavage product of the Ulp 1 protease to 5.6” Because how can pH of a product be adjusted is not clear. PH can be adjusted of solution containing the product.
clarity required.
Claim 9 is indefinite in reciting “hexafluoroisopropanol is hexafluoroisopropanol aqueous solution” make the claims unclear because of following reason:
A hexafluoroisopropanol is chemical; It itself cannot be aqueous solution. Makes no sense
Correction required.
Claim 10 is indefinite in reciting “hexafluoroisopropanol is hexafluoroisopropanol aqueous solution” make the claims unclear because of following reason:
A hexafluoroisopropanol is chemical; It itself cannot be aqueous solution. Makes no sense
Correction required.
Claim 11 is indefinite in reciting “a target polypeptide” lack antecedent basis. Claim 11 depends on claim 1. Claim 1 recitite polypeptide not a targegt polypeptide. Is it target polypeptide of claim 11 is the polypeptide of claim 1 and then which polypeptide it is. correction required.
Claim Rejections, 35 U.S.C 112(a) 1st Paragraph
The following is a quotation of the first paragraph of 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, 5-11 are rejected under 35 U.S.C. 112(a), first paragraph, as containing 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(s), at the time the application was filed, had possession of the claimed invention.
It is noted that MPEP 2111.01 states that "[d]uring examination, the claims must be interpreted as broadly as their terms reasonably allow." In this case, in light of the specification, the examiner has broadly interpreted the claims by reciting “preparation method comprises the following steps: constructing an engineering strain for fusion-expressing a polypeptide gene with a Sumo tag, and inducing the engineering strain to soluble-express the polypeptide; obtaining a fusion protein containing a polypeptide precursor from the engineering strain by purification; cleaving the fusion protein containing the polypeptide precursor by using a Ulp 1 protease’” comprise use of any an engineering strain having any structure from any source expressing any gene expressing a fusion protein having any structure . Therefore in light of the specification, claims are broadly interpreted to comprise any biological strain expressing any gene expressing any fusion protein capable of cleaving with UIp1 protease..
The Court of Appeals for the Federal Circuit has recently 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., 1997 U.S. App. LEXIS 18221, at *23, quoting Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993). To fully describe a genus of genetic material, which is a chemical compound, applicants must (1) fully describe at least one species of the claimed genus sufficient to represent said genus whereby a skilled artisan, in view of the prior art, could predict the structure of other species encompassed by the claimed genus and (2) identify the common characteristics of the claimed molecules, e.g., structure, physical and/or chemical characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or a combination of these (paraphrased from Enzo Biochemical).University of Rochester v. G.D. Searle & Co. (69 USPQ2d 1886 (2004)) specifically points to the applicability of both Lilly and Enzo Biochemical to methods of using products, wherein said products lack adequate written description. While in University of Rochester v. G.D. Searle & Co. the methods were held to lack written description because not a single example of the product used in the claimed methods was described, the same analysis applies wherein the product, used in the claimed methods, must have adequate written description (see Enzo paraphrased above).
There is no structure-function correlation with regard to the members of the genus of biological strain expressing any gene expressing any fusion protein having any structure and function capable of cleavable with UIp1 protease. Therefore one of skill in the art would not recognize from the disclosure that applicants were in possession of the claimed invention.
The genus of strain used in the used in the method of producing desired polypeptide precursor using any biological strain expressing any gene expressing any fusion protein capable of cleaving with UIp1 protease in the claimed invention is an extremely large structurally and functionally variable genus. An argument can be made pET-28a(+) or pET-22b(+) expression vector expressing any or more of the gene of SEQ ID NO: 1 , and SEQ ID NO:2 which is fusion of gene encoding of Nesiritide polypeptide with Sumo tag and also SEQ I NO:, 5, 6 . However, the art clearly teaches there is a practical limits to predict function of a polypeptide based structural homology:
A. Devos et al., (Proteins: Structure, Function and Genetics, 2000, Vol. 41: 98-107), teach that the results obtained by analyzing a significant number of true sequence similarities, derived directly from structural alignments, point to the complexity of function prediction. Different aspects of protein function, including (i) enzymatic function classification, (ii) functional annotations in the form of key words, (iii) classes of cellular function, and conservation of binding sites can only be reliably transferred between similar sequences to a modest degree. The reason for this difficulty is a combination of the unavoidable database inaccuracies and plasticity of proteins (Abstract, page 98) and the analysis poses interesting questions about the reliability of current function prediction exercises and the intrinsic limitation of protein function prediction (Column 1, paragraph 3, page 99) and conclude that "Despite widespread use of database searching techniques followed by function inference as standard procedures in Bioinformatics, the results presented here illustrate that transfer of function between similar sequences involves more difficulties than commonly believed. Our data show that even true pair-wise sequence relations, identified by their structural similarity, correspond in many cases to different functions (column 2, paragraph 2, and page 105).
B. Whisstock et al., (Quarterly Reviews of Biophysics 2003, Vol. 36 (3): 307-340,) also highlight the difficulties associated with "Prediction of protein function from protein sequence and structure": "To reason from sequence and structure to function is to step onto much shakier ground", closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function, in such cases, assignment of function on the basis of homology, in the absence of direct experimental evidence, will give the wrong answer (page 309, paragraph 4), it is difficult to state criteria for successful prediction of function, since function is in principle a fuzzy concept. Given three sequences, it is possible to decide which of the three possible pairs is most closely related. Given three structures, methods are also available to measure and compare similarity of the pairs. However, in many cases, given three protein functions, it would be more difficult to choose the pair with most similar function, although it is possible to define metrics for quantitative comparisons of different protein sequences and structures, this is more difficult for proteins of different functions (page 312, paragraph 5), in families of closely related proteins, mutations usually conserve function but modulate specificity i.e., mutations tend to leave the backbone conformation of the pocket unchanged but to affect the shape and charge of its lining, altering specificity (page 313, paragraph 4), although the hope is that highly similar proteins will share similar functions, substitutions of a single, critically placed amino acid in an active-site residue may be sufficient to alter a protein's role fundamentally (page 323, paragraph 1).
C. This finding is reinforced in the following scientific teachings for specific proteins in the art that suggest, even highly structurally homologous polypeptides do not necessarily share the same function and many functionally similar proteins will have little or no structural homology to disclosed proteins. For example, proteins having similar structure have different activities (structure does not always correlate to function); Witkowski et al., (Biochemistry 38:11643-11650, 1999) teaches that one conservative amino acid substitution transforms a beta -ketoacyl synthase into a malonyl decarboxylase and completely eliminates beta-ketoacyl synthase activity. The art also teaches that functionally similar molecules have different structures; Kisselev L., (Structure, 2002, Vol. 10: 8-9) teach that polypeptide release factors in prokaryotes and eukaryotes have same function but different structures.
As stated above, no information beyond the characterization of a few species; such as pET-28a(+) or pET-22b(+) expression vector expressing any or more of the gene of SEQ ID NO: 1 , and SEQ ID NO:2 which is fusion of gene encoding of Nesiritide polypeptide with Sumo tag and also SEQ I NO:, 5, 6 has been provided by the applicants’, which would indicate that they had the possession of the claimed invention . As it is discussed above, a minor changes in structure may result in changes affecting function, since, the specification provided no additional information (species/variant/mutant) correlating structure with function, one skilled in the art cannot reasonably conclude that applicant had possession of the claimed invention at the time the instant application was filed. Furthermore, "Possession may not be shown by merely describing how to obtain possession of members of the claimed ,genus or how to identify their common structural features" (See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895). A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the .gene does (function), rather what it is (structure), see University of California v. Eli Lilly & Co., 43 USPQ2d 1938, thus above claims lack adequate written description.
Applicants' are referred to the revised guidelines concerning compliance with the written description requirement of U.S.C. 112, first paragraph, published in the Official Gazette and also available at www.uspto.gov
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) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
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).
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 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.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
According to MPEP 2143:"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 predictableresults;(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."
Claims 1, 5-11 are rejected under 35 U.S.C. 103(a) as being unpatentable over D1: CN 101413009 A, IDS) in view of D2 ( otles protein removing process “ method of food analysisprotein removing process," Methods of Analysis of Food Components and Additives, Aug. 2008, 22 pages, (cited in International Search Report, IDS).
: And Rahimi et al. Applied to Amyloidogenic Peptides. J. Vis. Exp. (23), e1071, doi:10.3791/1071 (2009 and Xu et al. Anal Bioanal Chem (2017) 409:1281–1289Zahn et al. (wo2021/055366A1).
D1 discloses a method forpreparing a modified human amyloid polypeptide mutant-pramlintide. SUMOis used as a molecular chaperone to significantly increase the expression amount and solubility ofpramlintide, promoting the correct folding thereof, and an expressed fusion protein is obtained by purification by means of a purification tag. Then the SUMO and the tag are separated by means ofUlp1, so as to obtain a purified pramlintide. Under the action of a ubiquitin-related modifying factor protease, a fusion protein cuts down the pramlintide. A mixed solution carrier subjected to enzyme digestion is sent to a nickel column to remove small molecule ubiquitin-related modifying factor mature peptide impurities. The remaining pramlintide is further purified by means of gel filtration to obtain a purified pramlintide. Conditions suitable for expressing the fusion protein and ubiquitin-related modifying factor protease in a soluble form refer to induction for 5 hours at 37°C using 1 mmol/L of IPTG (see D1, description, page 1, paragraph 3, and page 3, paragraph 1 to page 4, last paragraph). [6] [6]
D1 docs not disclose purifying an enzyme digestion product by a method combining acetonitrile with heating precipitation or hexafluoroisopropanol precipitation.
D2 discloses that a protein is removed from a sample and a "non-protein substance" is separated from the protein. The following method can bc used: chemical precipitation, heat treatment precipitation, ultrafiltration, dialysis and column chromatography purification. For chemical protein removal, due to the fact that an organic solvent (ethanol, acetone and acetonitrile) can affect a spatial structure of a protein molecule, the hydrophobic interaction of the protein molecule is weakened, and the protein molecule directly reacts with a charged group on the surface of the protein molecule. Therefore, a molecular water layer is damaged, the protein is denatured, but the protein can be completely denatured only under the action of a high-concentration precipitant (65%-80%) for a long time (24 h) at a high temperature (20-30°C) (see page 42, paragraph 1 to page 43, last paragraph).
D1 and D2 docs not disclose purifying polypeptide product by a method hexafluoroisopropanol treatment.
It is well known in prior ats use of hexafluoroisopropanol ( Rahimi et al. Applied to Amyloidogenic Peptides. J. Vis. Exp. (23), e1071, doi:10.3791/1071 (2009 and Xu et al. Anal Bioanal Chem (2017) 409:1281–1289). And
Rahimi et al. teach peptides pre-treated with 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) to obtain homogeneous, aggregate-free preparations.
Xu et al. teach coacervate extraction method, based on hexafluoroisopropanol (HFIP)-induced catanionic surfactants and coupled with a back-extraction procedure, was developed for separation and purification of proteins ( abstract).
However, on the basis of the disclosure of D2, a person skilled in the art would be motivated to apply the method combining acetonitrile with heating precipitation to protein separation and purification in an enzyme digestion product. Morcover, hexafluoroisopropanol is also an organic solvent, and also can denature a protein. On the basis of the similar mechanism disclosed by D2, it can be expected that adding hexafluoroisopropanol also can achieve the purpose of protein separation and purification, thereby separating to obtain a small polypeptide, as prior ats teach use of hexafluoroisopropanol ( Rahimi et al. Applied to Amyloidogenic Peptides. J. Vis. Exp. (23), e1071, doi:10.3791/1071 (2009 and Xu et al. Anal Bioanal Chem (2017) 409:1281–1289) in protein purification..
Therefore it would have been obvious to a person of ordinary skill in the art, at the time of the instant invention is filled to combine the teaching of over D1: Senaratne et al. and D2: Zahn et al. , Rahimi et al. and Xu et al. and to the process of D1 use the teaching of D2: Zahn et al. , Rahimi et al. and Xu et al..to use engineering strain for fusion-expressing a polypeptide gene with a Sumo tag, and inducing the engineering strain to soluble-express the polypeptide; obtaining a fusion protein containing a polypeptide precursor from the engineering strain by purification; cleaving the fusion protein containing the polypeptide precursor by using a Ulp 1 protease to remove the Sumo tag; ( as taught by D1 and purifying a cleavage product of the Ulp 1 protease by a method of acetonitrile combined with heating precipitation as taught by D2 and use method of hexafluoroisopropanol to obtain the polypeptide as claimed by applicants claim 1, 5-11..
Conclusion
Claims 1-20 are rejected and no claim is allowable.
Any inquiry concerning this communication or earlier communications from the
examiner should be directed to Mohammad Meah whose telephone number is 571-272-
1261. The examiner can normally be reached on 8:30-5PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s
supervisor, Robert Mondesi can be reached on 4089187584. The fax phone number
for the organization where this application or proceeding is assigned is 571-273-8300.
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/MOHAMMAD Y MEAH/Examiner, Art Unit 1652
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