DETAILED ACTION
Status of the Application
Claims 25-44 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 without traverse of Group 14, claims 25-40 drawn in part to a chimeric protein that comprises a guided endonuclease protein, a linker, and a second protein, wherein said chimeric protein comprises SEQ ID NO: 51, as submitted in a communication filed on 9/25/2026 is acknowledged.
Upon alignment of SEQ ID NO: 51 against the proteins of SEQ ID NO: 1-3, 4-5 and 6-37, it has been found that SEQ ID NO: 51 comprises the Cas9 of SEQ ID NO: 1, the fluorescent protein of SEQ ID NO: 4 and the linker of SEQ ID NO: 18. In view of this, claims 30-31, 35, 37, 39 are directed to a non-elected invention.
Claims 30-31, 35, 37, 39, 41-44 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 9/25/2026.
Claims 25-29, 32-34, 36, 38, 40 are at issue and will be examined to the extent they encompass the elected invention.
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.
Priority
Acknowledgment is made of a claim for domestic priority under 35 U.S.C. 119(e) to provisional application No. 63/012,658 filed on 04/20/2020.
Acknowledgment is made of a claim for domestic priority under 35 U.S.C. 120 or 121 to US application No. 17/235,921 filed on 04/20/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 1/3/2025 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings submitted on 10/7/2024 have been reviewed and are accepted by the Examiner for examination purposes.
Claim Objections
Claim 27 is objected to due to the recitation of “group consisting of Cas9 protein, …protein…. protein……and a variant of Cas9….and …. protein”. To enhance clarity and to be consistent with commonly used claim language, the term should be amended to recite “…group consisting of a Cas9 protein, a….protein, a …..protein….., a variant of a Cas9 protein, a variant of a …protein….., and a variant of a …protein”. 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 25-29, 32-34, 36, 38, 40 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 25 (claims 26-29, 32-34, 36, 38, 40 dependent thereon) is indefinite in the recitation of “universal linker” for the following reasons. It is unclear as to what is encompassed by the term “universal linker” or the structure associated with a “universal” linker. Does the term refer to a protein linker, an oligonucleotide linker, a protein-oligonucleotide linker, or a chemical linker? For examination purposes, no patentable weight will be given to the term “universal”. Correction is required.
Claim 27 is indefinite in the recitation of “AsCas12a” and “LbCas12a” for the following reasons. It is unclear as to what these terms encompass. These terms do not convey a particular structure and/or function. For examination purposes, it will be assumed that these terms refer to Cas proteins and variants of Cas proteins. Correction is required.
Claim 28 is indefinite in the recitation of “..wherein the Cas protein is selected from the group comprising SEQ ID NO: 1, 2, and 3” for the following reasons. SEQ ID NO: 1, 2, and 3 are sequences, thus being graphical representations of the order in which amino acids are arranged. Therefore, it is unclear as to how a Cas protein is a sequence. In addition, the term “group comprising SEQ ID NO: 1, 2, and 3” is unclear because one cannot determine if the group can have other unknown members beyond SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3. It is noted that the term “comprising” is deemed open language. As such, one cannot determine if the Cas protein is limited only to the Cas protein of SEQ ID NO: 1, the Cas protein of SEQ ID NO: 2 or the Cas protein of SEQ ID NO: 3. If the intended group is one consisting of the Cas protein of SEQ ID NO: 1, the Cas protein of SEQ ID NO: 2 and the Cas protein of SEQ ID NO: 3, the claim should be amended accordingly. Correction is required.
Claim 29 is indefinite in the recitation of “wherein the Cas protein is SEQ ID NO: 1”. As known in the art, an amino acid sequence is a graphical representation of the order in which amino acids are arranged in a protein. Therefore, a protein is not an amino acid sequence. If the intended limitation is “wherein the Cas protein comprises/consists of SEQ ID NO: 1”, the claim should be amended accordingly. Correction is required.
Claim 33 is indefinite in the recitation of “….wherein the fluorescent protein is selected from the group comprising SEQ ID NO: 4 and 5” for the following reasons. SEQ ID NO: 4 and 5 are sequences, thus being graphical representations of the order in which amino acids are arranged. Therefore, it is unclear as to how a fluorescent protein is a sequence. In addition, the term “group comprising SEQ ID NO: 4 and 5” is unclear because one cannot determine if the group can have other unknown members beyond SEQ ID NO: 4 and SEQ ID NO: 5. It is noted that the term “comprising” is deemed open language. As such, one cannot determine if the fluorescent protein is limited only to the fluorescent protein of SEQ ID NO: 4 or the fluorescent protein of SEQ ID NO: 5. If the intended group is one consisting of the fluorescent protein of SEQ ID NO: 4, and the fluorescent protein of SEQ ID NO: 5, the claim should be amended accordingly. Correction is required.
Claim 34 is indefinite in the recitation of “wherein the fluorescent protein is SEQ ID NO: 4” for the following reasons. As known in the art, an amino acid sequence is a graphical representation of the order in which amino acids are arranged in a protein. Therefore, a protein is not an amino acid sequence. If the intended limitation is “wherein the fluorescent protein comprises/consists of SEQ ID NO: 4”, the claim should be amended accordingly. Correction is required.
Claim 36 (claim 38 dependent thereon) is indefinite in the recitation of “wherein the universal linker is selected from a flexible linker, a rigid linker and a mixed linker” for the following reasons. The term “mixed linker” is unclear in the absence of a statement indicating what is the intended meaning of the term “mixed”. Does the term “mixed” refer to proteins and nucleic acids? Does the term “mixed” refer to properties such as flexible and rigid? For examination purposes, no patentable weight will be given to the term “mixed linker”. Correction is required.
Claim 38 is indefinite in the recitation of “wherein the universal linker comprises a rigid linker selected from the group consisting of XP, APA, and SEQ ID NO: …..” for the following reasons. As indicated previously, the term “universal linker” is indefinite because it is unclear as to what is encompassed by the term “universal”. In addition, the terms “XP” and “APA” are unclear and confusing because one cannot determine if they refer to sequences associated with the linker (sequences that are required in the linker), or if these terms are labels. If they are labels, one cannot determine what they encompass as they do not convey a particular structure. Furthermore, if the linker is a protein, it is unclear as to how a protein linker can be an amino acid sequence such as SEQ ID NO: 18. As previously indicated, an amino acid sequence is a graphical representation of the order in which amino acids are arranged in a protein. For examination purposes, no patentable weight will be given to the terms “universal”, “XP” and “APA”. Correction is required.
Claim 40 is indefinite in the recitation of “wherein the chimeric protein is selected from the group consisting of SEQ ID NO: …51” for the following reasons. As previously indicated, an amino acid sequence is a graphical representation of the order in which amino acids are arranged in a protein. Therefore, a protein is not an amino acid sequence. If the intended limitation is a chimeric protein that comprises/consists of SEQ ID NO: 51, the claim should be amended accordingly. 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 25-27, 32-34, 36, 38 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 25-27, 32-34, 36, 38 are directed in part to a genus of fusion proteins that comprise a genus of guided endonucleases, Cas proteins or variants of a Cas protein having any structure. See Claim Rejections - 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 structural limitation with respect to the members of the genus of guided endonucleases, Cas proteins or variants of a Cas protein required by the claims. While the specification in the instant application discloses the structures of a limited number of Cas9 proteins that can be part of the claimed fusion proteins, it provides no clue as to the structural elements required in any guided endonuclease, Cas protein or variant of a Cas protein as required by the claims, nor does it teach which structural elements within the proteins disclosed are required in any guided endonuclease, Cas protein or variant of a Cas protein as required. No disclosure of a structure/function correlation has been provided which would allow one of skill in the art to recognize which proteins are guided endonucleases or Cas proteins so that they can be used in the claimed invention.
A sufficient written description of a genus of polypeptides may be achieved by a recitation of a representative number of polypeptides defined by their amino acid sequence or a recitation of structural features common to members of the genus, which constitute a substantial portion of the genus. However, in the instant case, there is no recited structural feature which is representative of all the members of the genus of proteins recited in the claims. There is no information as to which are the structural elements within the polypeptides disclosed in the specification that are essential for any guided endonuclease or Cas protein as required by the claimed fusion proteins. Furthermore, while one could argue that the few species disclosed are representative of the structure of all the members of the genus, it is noted that the art teaches several examples of how even highly structurally homologous polypeptides can have different enzymatic activities. For example, Witkowski et al. (Biochemistry 38:11643-11650, 1999; cited in the IDS) 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; cited in the IDS) teach that two Dehalobacter reductive dehalogenases, CfrA and DcrA, having 95.2% sequence identity to teach other have exclusively different substrate (Abstract; page 7, left column, Discussion, CfrA and DcrA). Seffernick et al. (J. Bacteriol. 183(8):2405-2410, 2001; cited in the IDS) 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 required by the claimed fusion proteins.
Due to the fact that the specification only discloses a limited number of species of the genus of proteins required by the claimed fusion proteins, 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 25-27, 32-34, 36, 38 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a fusion protein comprising SEQ ID NO: 51, or a fusion protein that comprises the Cas9 protein of SEQ ID NO: 1, the linker of SEQ ID NO: 18 and the protein of SEQ ID NO: 4, does not reasonably provide enablement for a fusion protein that comprises any guided endonuclease, any Cas protein or any variant of a Cas protein having any structure. 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 25-27, 32-34, 36, 38 broadly encompass a fusion protein that comprises any guided endonuclease, Cas protein or variant of a Cas protein that can have any structure. See Claim Rejections - 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 extremely large number of proteins of unknown structure encompassed by the claims. In the instant case, the specification enables a fusion protein that comprises SEQ ID NO: 51, and a fusion protein that comprises the Cas9 protein of SEQ ID NO: 1, the linker of SEQ ID NO: 18 and the protein of SEQ ID NO: 4.
The amount of direction or guidance presented and the existence of working examples. The specification discloses the amino acid sequence of a limited number of Cas9 proteins (SEQ ID NO: 1-3) as working examples. However, the specification fails to provide any clue as to the structural elements required in any guided endonuclease, Cas protein or variant of a Cas protein that is a guided endonuclease. There is no disclosure of the structural features within the polypeptides disclosed that can be modified and those that should be present for a variant of said polypeptides to have the desired activity. No correlation between structure and function has been presented.
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 Cas proteins, 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 guided endonuclease or any Cas protein. While the argument can be made that the structure of those proteins recited in the claims can be obtained 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; cited in the IDS) 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; cited in the IDS) 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 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 proteins to find a guided endonuclease, a Cas protein or a variant of a Cas protein that is a guided endonuclease. In the absence of (i) a rational and predictable scheme for selecting those proteins most likely to have the desired functional features, 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 to determine which ones have the desired functional characteristics.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 25-29, 32, 36, 38 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Liu et al. (U.S. Publication No. 2018/0312828 published 11/1/2018; effective filing date 3/23/2017).
Claims 25-29, 32, 36, 38 are directed in part to a fusion protein that comprises a Cas9 protein, a rigid linker, and a second protein, wherein said Cas9 protein can comprise SEQ ID NO: 1, wherein said rigid linker can comprise SEQ ID NO: 18, and wherein said second protein can be a fluorescent protein. See Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA ) for claim interpretation. Liu et al. teach fusion proteins that comprise the full-length of a Cas9 protein (page 25, paragraph [0224]), wherein said Cas9 protein is a wild-type S. pyogenes Cas9 protein that comprises the amino acid sequence of SEQ ID NO: 6 (page 23, paragraph [0219]), wherein said Cas9 fusion protein is fused to another protein via a rigid linker labeled (XP)n (SEQ ID NO: 611), wherein X is any amino acid, including alanine, and n is 1-30 (page 49, paragraph [0293]). Liu et al. teach that the fusion protein can comprise a green fluorescent protein (GFP; page 52, paragraph [0308]). Since SEQ ID NO: 18 is equivalent to (AP)9A, it follows that the rigid linker of Liu et al. where n = 10 and X is alanine comprises SEQ ID NO: 18. The Cas9 of SEQ ID NO: 6 is identical to the Cas9 of SEQ ID NO: 1 of the instant application as shown in the alignment below. Therefore, the fusion proteins of Liu et al. anticipate the instant claims as written/interpreted.
Query = SEQ ID NO:1 of the instant application
Sbjct = SEQ ID NO:6 of Liu et al.
NW Score Identities Positives Gaps
7005 1368/1368(100%) 1368/1368(100%) 0/1368(0%)
Query 1 MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAE 60
MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAE
Sbjct 1 MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAE 60
Query 61 ATRLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFG 120
ATRLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFG
Sbjct 61 ATRLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFG 120
Query 121 NIVDEVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSD 180
NIVDEVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSD
Sbjct 121 NIVDEVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSD 180
Query 181 VDKLFIQLVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGN 240
VDKLFIQLVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGN
Sbjct 181 VDKLFIQLVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGN 240
Query 241 LIALSLGLTPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAI 300
LIALSLGLTPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAI
Sbjct 241 LIALSLGLTPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAI 300
Query 301 LLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYA 360
LLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYA
Sbjct 301 LLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYA 360
Query 361 GYIDGGASQEEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELH 420
GYIDGGASQEEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELH
Sbjct 361 GYIDGGASQEEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELH 420
Query 421 AILRRQEDFYPFLKDNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEE 480
AILRRQEDFYPFLKDNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEE
Sbjct 421 AILRRQEDFYPFLKDNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEE 480
Query 481 VVDKGASAQSFIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFL 540
VVDKGASAQSFIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFL
Sbjct 481 VVDKGASAQSFIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFL 540
Query 541 SGEQKKAIVDLLFKTNRKVTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKI 600
SGEQKKAIVDLLFKTNRKVTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKI
Sbjct 541 SGEQKKAIVDLLFKTNRKVTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKI 600
Query 601 IKDKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWG 660
IKDKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWG
Sbjct 601 IKDKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWG 660
Query 661 RLSRKLINGIRDKQSGKTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSL 720
RLSRKLINGIRDKQSGKTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSL
Sbjct 661 RLSRKLINGIRDKQSGKTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSL 720
Query 721 HEHIANLAGSPAIKKGILQTVKVVDELVKVMGRHKPENIVIEMARENQTTQKGQKNSRER 780
HEHIANLAGSPAIKKGILQTVKVVDELVKVMGRHKPENIVIEMARENQTTQKGQKNSRER
Sbjct 721 HEHIANLAGSPAIKKGILQTVKVVDELVKVMGRHKPENIVIEMARENQTTQKGQKNSRER 780
Query 781 MKRIEEGIKELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYVDQELDINRLSDYDVDH 840
MKRIEEGIKELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYVDQELDINRLSDYDVDH
Sbjct 781 MKRIEEGIKELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYVDQELDINRLSDYDVDH 840
Query 841 IVPQSFLKDDSIDNKVLTRSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFDNL 900
IVPQSFLKDDSIDNKVLTRSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFDNL
Sbjct 841 IVPQSFLKDDSIDNKVLTRSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFDNL 900
Query 901 TKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDSRMNTKYDENDKLIREVKVITLKS 960
TKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDSRMNTKYDENDKLIREVKVITLKS
Sbjct 901 TKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDSRMNTKYDENDKLIREVKVITLKS 960
Query 961 KLVSDFRKDFQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFVYGDYKVYDVRK 1020
KLVSDFRKDFQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFVYGDYKVYDVRK
Sbjct 961 KLVSDFRKDFQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFVYGDYKVYDVRK 1020
Query 1021 MIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANGEIRKRPLIETNGETGEIVWDKGRDF 1080
MIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANGEIRKRPLIETNGETGEIVWDKGRDF
Sbjct 1021 MIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANGEIRKRPLIETNGETGEIVWDKGRDF 1080
Query 1081 ATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIARKKDWDPKKYGGFDSPTVA 1140
ATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIARKKDWDPKKYGGFDSPTVA
Sbjct 1081 ATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIARKKDWDPKKYGGFDSPTVA 1140
Query 1141 YSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLIIKLPK 1200
YSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLIIKLPK
Sbjct 1141 YSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLIIKLPK 1200
Query 1201 YSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASHYEKLKGSPEDNEQKQLFVE 1260
YSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASHYEKLKGSPEDNEQKQLFVE
Sbjct 1201 YSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASHYEKLKGSPEDNEQKQLFVE 1260
Query 1261 QHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAENIIHLFTLTNLGA 1320
QHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAENIIHLFTLTNLGA
Sbjct 1261 QHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAENIIHLFTLTNLGA 1320
Query 1321 PAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQLGGD 1368
PAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQLGGD
Sbjct 1321 PAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQLGGD 1368
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.
Claim Rejections - 35 USC § 103 (AIA )
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 of this title, 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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 33-34 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (U.S. Publication No. 2018/0312828 published 11/1/2018; effective filing date 3/23/2017) in view of Liu et al. (Cell Discovery 1, 15007, pages 1-11, published online 5/12/2015; hereinafter “Liu 2”).
The teachings of Liu et al. have been discussed above. Liu et al. do not teach a fusion protein comprising a Cas9 protein and enhanced green fluorescent protein (eGFP). Liu 2 teaches a fusion protein that comprises a Cas9 protein and eGFP to detect expression and localization of the Cas9 protein (page 2, right column, last 6 lines). The specification of the instant application discloses that eGFP comprises SEQ ID NO: 4. Therefore, it follows that in the absence of evidence to the contrary, the eGFP of Liu 2 also comprises SEQ ID NO: 4. Liu 2 does not teach a rigid linker that comprises SEQ ID NO: 18.
Claims 33-34 are directed in part to the fusion protein of claim 32 as described above, wherein the fluorescent protein comprises SEQ ID NO: 4.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the eGFP protein of Liu 2 in the fusion protein of Liu et al. A person of ordinary skill in the art is motivated to use the eGFP protein in the fusion protein of Liu et al. because this fluorescent protein is a well-known fluorescent protein used for detection of proteins such as a Cas9 protein. One of ordinary skill in the art has a reasonable expectation of success at using the eGFP protein of Liu 2 in the fusion of Liu et al. because the methods to produce such protein are well known in the art as evidenced by Liu 2 who discloses the manufacture of a fusion protein that comprises a Cas9 protein and eGFP. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art at the time the invention was made.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 25-29, 32-34, 36, 38, 40 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,152,258. Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons.
Claims 25-29, 32-34, 36, 38, 40 of the instant application are directed in part to a chimeric protein that comprises the Cas9 protein of SEQ ID NO: 1, the fluorescent protein of SEQ ID NO: 4 and a linker that comprises the amino acid sequence APA, including the amino acid sequence of SEQ ID NO: 16, wherein said chimeric protein can comprise SEQ ID NO: 49. See Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA ) for claim interpretation.
Claim 1 of U.S. Patent No. 12,152,258 is directed to a chimeric protein that comprises SEQ ID NO: 49. SEQ ID NO: 49, SEQ ID NO: 1, SEQ ID NO: 4 and SEQ ID NO: 16 of U.S. Patent No. 12,152,258 are identical to SEQ ID NO: 49, SEQ ID NO: 1, SEQ ID NO: 4, and SEQ ID NO: 16 of the instant application. SEQ ID NO: 49 comprises SEQ ID NO: 1, SEQ ID NO: 4 and SEQ ID NO: 16. Therefore, the protein of claim 1 of U.S. Patent No. 12,152,258 anticipates the chimeric protein of claims 25-29, 32-34, 36, 38, 40 of the instant application.
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
October 12, 2026
