DETAILED ACTION
Response to Amendment
Applicant’s response to the office action filed on November 5, 2025 has been entered. The claims pending in this application are claims 1-21. The objections and rejections not reiterated from the previous office action are hereby withdrawn in view of applicant’s amendment filed on November 5, 2025. Claims 1-21 will be examined.
Drawings
New Figures 7A and 7B have been accepted and entered. However, some words in Figure 8B cannot be recognized. Applicant is required to submit a new Figure 8B. No new matter may be introduced in the required drawing. The drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d).
Nucleotide and/or Amino Acid Sequence Disclosures
Specific deficiency – Several nucleotide sequences appearing in Figure 4 have more than 10 nucleotides and are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objections
Claim 1 or 11 or 21 is objected to because of the following informality: “the alternative sequence is derived comprising synonymous codon substitution” in replacing step should be “the alternative sequence comprises synonymous codon substitutions”.
Claim 3 or 13 is objected to because of the following informality: “any such detected plurality of homologous sequences and plurality of identical sequences” should be “the detected plurality of homologous sequences and plurality of identical sequences which may cause an undesired variant in the gene construct”.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-21 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims have been evaluated using the 2019 Revised Patent Subject Matter Eligibility Guidance (see Federal Register Vol. 84, No. 4 Monday, January 7, 2019).
Step 1: The claims are directed to the statutory category of a process.
Step 2A, prong one: Evaluate Whether the Claim Recites a Judicial Exception
The instant claims recite a law of nature. The claims recite detecting and replacing a sequence which may cause an undesired variant in a gene construct and creating a gene product used in cell therapy. This type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo.
The instant claims recite abstract ideas. Claims 1-21 recite replacing the detected sequence which may cause the undesired variant with an alternative sequence, wherein the alternative sequence comprises synonymous codon substitutions, and repeating the replacing steps if the frequency percentage of the undesired variant in the gene product from the in-vivo analysis is greater than a predetermined value of acceptable frequency percentage of the undesired variant. The “replacing” step in claims 1, 11, and 21 encompasses a step that can be accomplished by a mental processes. For example, one may “replacing” the detected sequence which may cause the undesired variant with an alternative sequence comprising synonymous codon substitution by writing down a replaced alternative sequence comprising synonymous codon substitutions using a pen based on known nucleotide codes of amino acids.
Claim 1 recites a “wherein” phrase that the predetermined value of acceptable frequency percentage of undesired variant is determined based on the undesired variant being associated with the undesired variant negatively impacting exportation of the chimeric antigen receptor to a cell surface, claim 17 recites a “wherein” phrase that the predetermined value of acceptable frequency percentage of undesired variant is determined based on whether the undesired variant is associated with at least one of whether the undesired variant negatively impacts exportation of the chimeric antigen receptor to a cell surface, whether the undesired variant is associated with changes to a binding domain of the chimeric antigen receptor, and whether the undesired variant has been previously characterized as causing a negligible impact on the expression or function of the chimeric antigen receptor, and claim 21 recites a “wherein” phrase that the predetermined value of acceptable frequency percentage of undesired variant is determined based on the undesired variant being associated with changes to a binding domain of the chimeric antigen receptor. However, claims 1, 17, and 21 do not set forth how these “wherein” phrases are accomplished. The “wherein” phrase in claim 1 can be accomplished by a mental processes based on comparing the undesired variant with the undesired variant negatively impacting exportation of the chimeric antigen receptor to a cell surface. For example, one may “compare” the undesired variant with the undesired variant negatively impacting exportation of the chimeric antigen receptor to a cell surface by reading a laboratory report having properties of different undesired variants side by side and identifying an undesired variant being associated with the undesired variant negatively impacting exportation of the chimeric antigen receptor to a cell surface. The “wherein” phrase in claim 17 can be accomplished by a mental processes based on comparing the undesired variant with the undesired variant negatively impacting exportation of the chimeric antigen receptor to a cell surface or the undesired variant associated with changes to a binding domain of the chimeric antigen receptor or the undesired variant which has been previously characterized as causing a negligible impact on the expression or function of the chimeric antigen receptor. For example, one may “compare” the undesired variant with the undesired variant negatively impacting exportation of the chimeric antigen receptor to a cell surface or the undesired variant associated with changes to a binding domain of the chimeric antigen receptor or the undesired variant which has been previously characterized as causing a negligible impact on the expression or function of the chimeric antigen receptor by reading a laboratory report having properties of different undesired variants side by side and identifying an undesired variant negatively impacting exportation of the chimeric antigen receptor to a cell surface or the undesired variant associated with changes to a binding domain of the chimeric antigen receptor or the undesired variant which has been previously characterized as causing a negligible impact on the expression or function of the chimeric antigen receptor. The “wherein” phrase in claim 21 can be accomplished by a mental processes based on comparing different undesired variants. For example, one may “compare” different undesired variant by reading a laboratory report having properties of different undesired variants side by side and identifying an undesired variant being associated with changes to a binding domain of the chimeric antigen receptor.
For the reasons discussed above, the “replacing” step in claims 1, 11, and 21 and “wherein” phrase in claims 1, 17, and 21 could be performed by a human using mental steps or basic critical thinking, which are types of activities that have been found by the courts to represent abstract ideas (e.g., the mental comparison in Ambry Genetics or the diagnosing an abnormal condition by performing clinical tests and thinking about the results in Grams).
Step 2A, prong two: Evaluate Whether the Judicial Exception Is Integrated Into a Practical Application
Since it is known that in biology and other experimental sciences, an in silico experiment is one performed on a computer or via computer simulation software (see “in silico” from Wikipedia), the in-silico analysis in “performing” and “repeating” steps of claims 1, 11, and 21 broadly encompasses an analysis step that can be accomplished by a general computer. Since splice-aware aligners are just BWA-base aligners wrapped in additional code to take into accounts split or distant pair alignments (see “Splice-Aware Aligners”), the frequency percentage of the undesired variant is determined at least in part by using a splice-aware aligner from the RNA-sequencing analysis in “measuring” step of claims 1 and 21 and in two “measuring” steps of claim 11 can be accomplished by a general computer. Therefore, claims 1, 11, and 21 do NOT recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). For example, claims 1, 11, and 21 do not show that, compared with closest prior arts, in-silico analysis can be performed in a faster or/and better or/and cheaper way in the claimed invention. It is important to note that a general purpose computer that applies a judicial exception, such as an abstract idea, by use of conventional computer functions does not qualify as a particular machine and merely adding generic computer components to perform the method is not sufficient (see MPEP 2106.05). Performing an abstract idea on a generic computer is not an additional element that is significantly more than the abstract idea itself. In Alice Corp. Pty. Ltd. v. CLS Bank Int'l (573 U.S. 134 S.Ct. 2347, 110 USPQ2d 1976 (2014)) the Supreme Court stated regarding claims directed to an abstract idea:
These cases demonstrate that the mere recitation of a generic computer cannot transform a patent-ineligible abstract idea into a patent-eligible invention. Stating an abstract idea “while adding the words ‘apply it’” is not enough for patent eligibility. Mayo, supra, at ___ (slip op., at 3). Nor is limiting the use of an abstract idea “‘to a particular technological environment.’” Bilski, supra, at 610–611. Stating an abstract idea while adding the words “apply it with a computer” simply combines those twosteps, with the same deficient result. Thus, if a patent’s recitation of a computer amounts to a mere instruction to “implemen[t]” an abstract idea “on . . . a computer,” Mayo, supra, at ___ (slip op., at 16), that addition cannot impart patent eligibility. This conclusion accords with the pre-emption concern that undergirds our §101 jurisprudence. Given the ubiquity of computers, see 717 F. 3d, at 1286(Lourie, J., concurring), wholly generic computer implementation is not generally the sort of “additional featur[e]” that provides any “practical assurance that the process is more than a drafting effort designed to monopolize the [abstract idea] itself.” Mayo, 566 U. S., at ___ (slip op., at 8–9).
Regarding claims to computers and computer-readable media that execute an abstract idea, the court further stated:
Petitioner’s claims to a computer system and a computer-readable medium fail for substantially the same reasons. Petitioner conceded below that its media claims rise or fall with its method claims. En Banc Response Brief for Defendant-Appellant in No. 11–1301 (CA Fed.) p. 50, n. 3. As to its system claims, petitioner emphasizes that those claims recite “specific hardware” configured to perform “specific computerized functions.” Brief for Petitioner 53. But what petitioner characterizes as specific hardware-a “data processing system” with a “communications controller” and “data storage unit,” for example, see App. 954,958, 1257-is purely functional and generic. Nearly every computer will include a “communications controller” and “data storage unit” capable of performing the basic calculation, storage, and transmission functions required by the method claims. See 717 F. 3d, at 1290 (Lourie, J., concurring). As a result, none of the hardware recited by the system claims “offers a meaningful limitation beyond generally linking ‘the use of the [method] to a particular technological environment,’ that is, implementation via computers.” Id., at 1291 (quoting Bilski, 561 U. S., at 610–611). Put another way, the system claims are no different from the method claims in substance. The method claims recite the abstract idea implemented on a generic computer; the system claims recite a handful of generic computer components configured to implement the same idea. This Court has long “warn[ed] . . . against” interpreting §101 “in ways that make patent eligibility ‘depend simply on the draftsman’s art.’” Mayo, supra, at ___ (slip op., at 3) (quoting Flook, 437 U. S., at 593); see id., at 590 (“The concept of patentable subject matter under §101 is not ‘like a nose of wax which may be turned and twisted in any direction . . . ’”). Holding that the system claims are patent eligible would have exactly that result.
Because petitioner’s system and media claims add nothing of substance to the underlying abstract idea, we hold that they too are patent ineligible under §101.
The claims do not practically apply the judicial exception by including one or more additional elements that the courts have stated integrate the exception into a practical application:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
An additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
An additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
An additional element effects a transformation or reduction of a particular article to a different state or thing; and
An additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
Step 2B: Evaluate Whether the Claim Provides an Inventive Concept
In addition to the judicial exception claims 1 and 21 recite an additional step “measuring a frequency percentage of the undesired variant expressed by the gene construct comprising performing an in-vivo analysis of one or more genes expressed by the gene construct comprising performing a RNA-sequencing analysis of an RNA product transcribed from the gene construct wherein the frequency percentage of the undesired variant is determined at least in part by using a splice-aware aligner from the RNA- sequencing analysis” and claim 11 recites additional steps “measuring a frequency percentage of the undesired variant expressed by the gene construct comprising performing an in-vivo analysis of one or more genes expressed by the gene construct comprising performing a RNA-sequencing analysis of an RNA product transcribed from the gene construct wherein the frequency percentage of the undesired variant is determined at least in part by using a splice-aware aligner from the RNA- sequencing analysis” and “measuring a frequency percentage of the undesired variant expressed by the new gene construct comprising performing an in-vivo analysis of one or more genes expressed by the new gene construct comprising performing a RNA-sequencing analysis of an RNA product transcribed from the new gene construct wherein the frequency percentage of the undesired variant is determined at least in part by using a splice-aware aligner from the RNA- sequencing analysis”. These additional elements in claims 1, 11, and 21 do not amount to significantly more because they simply append well understood, routine, and conventional activities previously known in the art, specified at a high level of generality, to the judicial exceptions.
These prior arts demonstrate the well understood, routine, conventional nature of the additional elements because they teach that the additional steps are well known in the art. For example, it is known that a frequency percentage of the undesired variant expressed by a gene construct can be measured by performing an in-vivo analysis of one or more genes expressed by the gene construct (ie., a transgene) and performing an in vitro RNA-sequencing analysis of an RNA product transcribed from the gene construct (see paragraphs [0314], [0316], [0343], [0354], and [0355] from Sather et al., US 2019/0161553 A1, published on May 30, 2019) and the frequency percentage of undesired variant can be determined at least in part by using a splice-aware aligner from the RNA-sequencing analysis (see abstract, page 2, last paragraph, page 3, first paragraph, page 5 last paragraph bridging to page 6, first paragraph and Figure 4 from Hong et al., PLOS One, 13 (8), e0201822, 2018).
Further it is noted that the courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
• Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014).
For the reasons set forth above the claims are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Scope Of Enablement
Claims 1-21 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 performing an in-siloco analysis of a gene construct, does not reasonably provide enablement for performing the methods recited in claims 1-21. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the 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 Nature of The Invention
The claims are drawn to a method for detecting and replacing a sequence which may cause an undesired variant in a gene construct and a method for creating a gene product used in cell therapy. The invention is a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The Breadth of The Claims
Claims 1-10 encompass a method for detecting and replacing a sequence which may cause an undesired variant in a gene construct, comprising: performing an in-silico analysis of the gene construct to detect a presence of the sequence which may cause the undesired variant;
replacing the detected sequence which may cause the undesired variant with an alternative sequence, wherein the alternative sequence comprises synonymous codon substitutions; measuring a frequency percentage of the undesired variant expressed by the gene construct comprising performing an in-vivo analysis of one or more genes expressed by the gene construct comprising performing a RNA-sequencing analysis of an RNA product transcribed from the gene construct, wherein the frequency percentage of the undesired variant is determined at least in part by using a splice-aware aligner from the RNA-sequencing analysis; and repeating the in-silico analysis and replacing steps if the frequency percentage of the undesired variant in the gene product from the in-vivo analysis is greater than a predetermined value of acceptable frequency percentage of the undesired variant; and wherein the predetermined value of acceptable frequency percentage of undesired variant is determined based on the undesired variant being associated with the undesired variant negatively impacting exportation of the chimeric antigen receptor to a cell surface. Claims 11-20 encompass a method for creating a gene product used in cell therapy, comprising: performing an in-silico analysis on a gene construct encoding said gene product to identify and alter a sequence that may causes an undesired variant;
replacing the detected sequence which may cause the undesired variant with an alternative sequence, wherein the alternative sequence comprises synonymous codon substitutions;
measuring a frequency percentage of the undesired variant expressed by the gene construct comprising performing an in-vivo analysis of one or more genes expressed by the gene construct comprising performing a RNA-sequencing analysis of an RNA product transcribed from the gene construct, wherein the frequency percentage of the undesired variant is determined at least in part by using a splice-aware aligner from the RNA-sequencing analysis; repeating the in-silico and replacing steps to create a new gene construct if the frequency percentage of the undesired variant in the gene product from the in-vivo analysis is greater than a predetermined value of acceptable frequency percentage of the undesired variant; and measuring a frequency percentage of the undesired variant expressed by the new gene construct comprising performing an in-vivo analysis of one or more genes expressed by the new gene construct comprising performing a RNA-sequencing analysis of an RNA product transcribed from the new gene construct, wherein the frequency percentage of the undesired variant is determined at least in part by using a splice- aware aligner from the RNA-sequencing analysis. Claim 21 encompasses a method for detecting and replacing a sequence which may cause an undesired variant in a gene construct, comprising: performing an in-silico analysis of the gene construct to detect a presence of the sequence which may cause the undesired variant; replacing the detected sequence which may cause the undesired variant with an alternative sequence, wherein the alternative sequence comprises synonymous codon substitutions; measuring a frequency percentage of the undesired variant expressed by the gene construct comprising performing an in-vivo analysis of one or more genes expressed by the gene construct comprising performing a RNA-sequencing analysis of an RNA product transcribed from the gene construct, wherein the frequency percentage of the undesired variant is determined at least in part by using a splice-aware aligner from the RNA-sequencing analysis; and repeating the in-silico analysis and replacing steps if the frequency percentage of the undesired variant in the gene product from the in-vivo analysis is greater than a predetermined value of acceptable frequency percentage of the undesired variant; and wherein the predetermined value of acceptable frequency percentage of undesired variant is determined based on the undesired variant being associated with changes to a binding domain of the chimeric antigen receptor.
Working Examples
Although the specification provides six working examples (see paragraphs [0179] to [0192] of US 2023/0103457 A1, which is US publication of this instant case), the specification provides no working example for performing the methods recited in claims 1-21.
The Amount of Direction or Guidance Provided and The State of The Prior Art
The specification provides six working examples (see paragraphs [0179] to [0192] of US 2023/0103457 A1, which is US publication of this instant case). However, the specification provides no working example for performing the methods recited in claims 1-21.
Level of Skill in The Art, The Unpredictability of The Art, and The Quantity of Experimentation Necessary
While the relative skill in the art is very high (the Ph.D. degree with laboratory experience), there is no predictability whether the methods recited in claims 1-21 can be performed.
First, although the specification teaches performing an in-vivo analysis of one or more genes expressed by the gene construct comprising performing a RNA-sequencing analysis of an RNA product transcribed from the gene construct (see paragraphs [0013], [0014], [0105], [0116], [0127], [0179], and [0183] of US 2023/0103457 A1, which is US publication of this instant case), nowhere in the specification shows what in-vivo analysis of one or more genes expressed by the gene construct can comprise performing a RNA-sequencing analysis of an RNA product transcribed from the gene construct. Since it is known that “[S]tudies that are in vivo (Latin for ‘within the living’; often not italicized in English[1][2][3]) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually
animals, including humans, and plants, as opposed to a tissue extract or dead organism” (see the definition for “In vivo” from Wikipedia) and a RNA-sequencing analysis of an RNA product transcribed from the gene construct is an in vitro process, and the specification and available arts do not indicate how a RNA-sequencing analysis of an RNA product transcribed from the gene construct can be performed inside of whole living organisms or animals or plants, it is unpredictable how a frequency percentage of the undesired variant expressed by the gene construct can be measured by performing an in-vivo analysis of one or more genes expressed by the gene construct comprising performing a RNA-sequencing analysis of an RNA product transcribed from the gene construct as recited in claims 1-21 and how a frequency percentage of the undesired variant expressed by the new gene construct can be measured by performing an in-vivo analysis of one or more genes expressed by the new gene construct comprising performing a RNA-sequencing analysis of an RNA product transcribed from the new gene construct as recited in claims 11-20. Furthermore, although claim 1 requires that the predetermined value of acceptable frequency percentage of undesired variant is determined based on the undesired variant being associated with the undesired variant negatively impacting exportation of the chimeric antigen receptor to a cell surface, since claim 1 does not require that undesired variant is a chimeric antigen receptor of a cell surface and does not indicate what kind of undesired variant is read as the undesired variant negatively impacting exportation of the chimeric antigen receptor to a cell surface, it is unpredictable how the predetermined value of acceptable frequency percentage of undesired variant used as a comparison control of the frequency percentage of the undesired variant in the gene product from the in-vivo analysis can be determined based on the undesired variant being associated with the undesired variant negatively impacting exportation of the chimeric antigen receptor to a cell surface as recited in claims 1-7, 9, and 10 and based on whether the undesired variant is associated with whether the undesired variant negatively impacts exportation of the chimeric antigen receptor to a cell surface as recited in claim 17, how the predetermined value of acceptable frequency percentage of the undesired variant can be 0.1% if the undesired variant negatively impacts exportation of the chimeric antigen receptor to a cell surface, and how the predetermined value of acceptable frequency percentage of the undesired variant can be 0.01% if the undesired variant is associated with changes to a binding domain of the chimeric antigen receptor as recited in claims 8 and 18. In addition, since claim 21 does not require that undesired variant is a chimeric antigen receptor of a cell surface and does not indicate that, in which situation, an undesired variant is considered to be associated with changes to a binding domain of the chimeric antigen receptor, it is unpredictable how the predetermined value of acceptable frequency percentage of undesired variant used as a comparison control of the frequency percentage of the undesired variant in the gene product from the in-vivo analysis can be determined based on the undesired variant being associated with changes to a binding domain of the chimeric antigen receptor as recited in claim 21 and based on whether the undesired variant has been previously characterized as causing a negligible impact on the expression or function of the chimeric antigen receptor as recited in claim 17.
Second, although it is known that “a synonymous substitution (often called a silent substitution though they are not always silent) is the evolutionary substitution of one base for another in an exon of a gene coding for a protein, such that the produced amino acid sequence is not modified” (see the definition for “a synonymous substitution” from Wikipedia), the synonymous codons can be considered as different three-letter DNA or RNA sequences (triplets) that code for the exact same amino acid. Since the specification and available arts do not indicate what is a sum of a matrix of subsection combinations from the gene construct and what synonymous codons are random synonymous codons, it is unpredictable how the plurality of alternative sequences can increase the sum of the matrix by substituting a plurality of random synonymous codons in the gene construct with a plurality of alternative sequences as recited in claim 5 or 15.
Third, since the specification does not indicate which undesired variant can be considered as the undesired variant causing a negligible impact on the expression or function of the chimeric antigen receptor, it is unpredictable how the repeating the in-silico analysis and replacing steps cannot be performed if the undesired variant has been previously characterized as causing a negligible impact on the expression or function of the chimeric antigen receptor as recited in claim 9 or 19.
Fourth, since the specification does not indicate which analysis is used for determining whether the subpopulation of low-frequency variants is replaced, it is unpredictable how conducing any kind of analysis can determine whether the subpopulation of low-frequency variants should be replaced as recited in claim 10 or 20.
Fifth, since the specification does not indicate which undesired variant can be considered as the undesired variant causing a negligible impact on the expression or function of the chimeric antigen receptor, it is unpredictable how the predetermined value of acceptable frequency percentage of undesired variant can be determined based on whether the undesired variant has been previously characterized as causing a negligible impact on the expression or function of the chimeric antigen receptor as recited in claim 17.
Case law has established that “(t)o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation’.” In re Wright 990 F.2d 1557, 1561. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) it was determined that “[T]he scope of the claims must bear a reasonable correlation to the scope of enablement provided by the specification to persons of ordinary skill in the art”. The amount of guidance needed to enable the invention is related to the amount of knowledge in the art as well as the predictability in the art. Furthermore, the Court in Genentech Inc. v Novo Nordisk 42 USPQ2d 1001 held that “[I]t is the specification, not the knowledge of one skilled in the art that must supply the novel aspects of the invention in order to constitute adequate enablement”.
In view of above discussions, the skilled artisan will have no way to predict the experimental results. Accordingly, it is concluded that undue experimentation is required to make the invention as it is claimed. The undue experimentation at least includes to test whether the methods recited in claims 1-21 can be performed.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-21 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 or 21 recites the limitation “the chimeric antigen” in last line of the claim. There is insufficient antecedent basis for this limitation in the claim because there is no phrase “a chimeric antigen” before “the chimeric antigen”. Please clarify.
Claim 1 or 11 or 21 is rejected as vague and indefinite because it is unclear that performing a RNA-sequencing analysis of an RNA product transcribed from the gene construct in claim 1 or 11 or 21 and performing a RNA-sequencing analysis of an RNA product transcribed from the new gene construct are in-vivo arrays in vitro arrays. Please clarify.
Claim 4 or 14 is rejected as vague and indefinite because it is unclear what means a sum of a matrix of subsection combinations from the gene construct. Please clarify.
Claim 5 or 15 is rejected as vague and indefinite. Although it is known that “a
synonymous substitution (often called a silent substitution though they are not always silent) is the evolutionary substitution of one base for another in an exon of a gene coding for a protein, such that the produced amino acid sequence is not modified” (see the definition for “a
synonymous substitution” from Wikipedia), the synonymous codons can be considered as different three-letter DNA or RNA sequences (triplets) that code for the exact same amino acid. Since the specification and available arts do not have a definition for “random synonymous codons”, it is unclear what means “random synonymous codons”. Please clarify.
Conclusion
Note that the rejections on claims 11-20 under 35 U.S.C 103 have been withdrawn since the office now considers that performing a RNA-sequencing analysis of an RNA product transcribed from the gene construct in claim 1 or 11 or 21 and performing a RNA-sequencing analysis of an RNA product transcribed from the new gene construct in claim 11 are in-vivo assays (see above Scope Of Enablement rejection). If performing a RNA-sequencing analysis of an RNA product transcribed from the gene construct in claim 1 or 11 or 21 and performing a RNA-sequencing analysis of an RNA product transcribed from the new gene construct in claim 11 become in vitro assays based on applicant’s amendment, at least claim 11 can be rejected under 35 U.S.C 103 based on a combination of Sather et al., (US 2019/0161553 A1, published on May 30, 2019) and Hong et al., (POLS One, 13(8), e0201822, 2018) (see the non-final rejection mailed on August 7, 2025).
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Frank Lu, Ph. D., whose telephone number is (571)272-0746. The examiner can normally be reached Monday to Friday, 9 AM to 5 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/ interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Anne Gussow, Ph.D., can be reached at 571-272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/FRANK W LU/Primary Examiner, Art Unit 1683 August 7, 2026
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