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 .
Detailed Action
Claims 1 – 4, 29 – 32, and 46 - 52 are currently pending in the instant application.
Restriction/Election
Applicant's elected, in the reply filed June 4, 2026 of Group I, claims 1- 5, and 29 – 32, directed to a method for determining the potency of IL-2 analog, without traverse.
Claims 11 – 13, 19 – 20, 23 – 26, 36 – 37, and 43 have been canceled by Applicants’ amendment filed on 6/4/2026 and claims 46 – 52 have been newly added by Applicants’ amendment filed on 6/4/2026.
The restriction requirement filed on 5/29/2026 is still deemed proper and is therefore made FINAL.
Therefore, claims 1 – 4, 29 – 32, and 46 - 52 are under consideration to which the following grounds of rejection are applicable. Claims 1 and 29 are independent claims.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on April 18, 2025, and February 26, 2026 has been considered. An initialed copy of the IDS accompanies this Office Action.
Priority
The present application filed November 28, 2023, is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2022/031872, filed June 2, 2022, which claims the benefit of Provisional Application 63/330,817, filed April 14, 2022, which claims the benefit of Provisional Application 63/208,223, filed June 8, 2021.
Therefore, the earliest priority date is June 8, 2021.
Claim Rejection - 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.
Claims 1 – 4, 29 – 32, and 46 - 54 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.
Claims 1 and 29 are indefinite for the recitation of “the potency,” such as recited in claim 1, in line 1. There is a lack of antecedent basis for the term “the potency.”
Claims 1 and 29 are indefinite in its recitation of “comprising a STATS response element and a promoter”. The practitioner in the art would readily understand that response elements are located within promoters and are short DNA sequences that bind specific transcription factors to regulate gene expression in response to stimuli. Thus, it is unclear where the STATS response is located. As such the metes and bounds of the claim are indefinite.
Claim 2 is vague and indefinite in the recitation of “…capable of…” , since this phrase refers to a latent ability, and it is unknown whether the ability is expressed or observed in the invention.
Note, it has been held that the recitation that an element is “capable of” performing a function is not a positive limitation, but only requires the ability to so perform. It does not constitute a limitation in any patentable sense. In re Hutchinson, 69 USPQ 138.
Claim 3 is vague and indefinite in the recitation of “…capable of…” in lines 1 , 4, 5 and 10 since this phrase refers to a latent ability, and it is unknown whether the ability is expressed or observed in the invention.
Claim 48 is vague and indefinite in the recitation of “…capable of…” , since this phrase refers to a latent ability, and it is unknown whether the ability is expressed or observed in the invention.
Claim 49 is indefinite in its recitation of “the IL-2 analog biased…. comprises at least one amino acid substitution or deletion that reduces or eliminates binding to the IL-2Ra~y complex” . The term “reduces” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Moreover, it is unclear in relation to what the IL-2 analog biased for the IL-2R~y complex is relative to.
Claim 50 is indefinite in its recitation of “the IL-2 analog biased…. comprises at least one non-natural amino acid substitution that reduces or eliminates binding to the IL-2Ra~y complex” . The term “reduces” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Moreover, it is unclear in relation to what the IL-2 analog biased for the IL-2R~y complex is relative to.
Claim 47 and 53 are indefinite for the recitation of “one or more copies of the nucleotide sequence TCCNNNGAA wherein N is independently any nucleotide,” such as recited in claim 47, in lines 1 – 3. It is unclear what exactly is the sequence of the Stat5 response element that is being used in the cells, and thus, the metes and bounds of the claim cannot be determined.
Claims 4, and 51 are indefinite insofar as they ultimately depend from claim 1.
Claims 30 – 32, 52, and 54 are indefinite insofar as they ultimately depend from claim 29.
Claim Rejection - 35 USC § 112(a) Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1 – 4, 29 – 32, and 46 - 54 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 method for determining the potency of an IL-2 analog biased for IL-2Rβγ complex over the IL-2Rαβγ complex, comprising:
Providing (i) CD25 K/O Kit225 STAT5 cell line that expresses an IL-2Rβγ complex without
expression of an IL-2Rαβγ complex, a STAT5 response element within a promoter which is linked to an open reading frame encoding a luciferase reporter protein, and (ii) serial dilutions of an IL-2 analog biased for IL-2Rβγ complex,
wherein STAT5 response element comprises five copies of the 9-mer. SEQ ID NO: 1,
and wherein the STAT5 responsive reporter system comprises a dimerized STAT5a, wherein dimerized STAT5 translocate to the nucleus and binds to the STAT5 response element (TTCNNNGAA).Contacting each serial dilution of the IL-2 analog biased for the IL-2Rβγ complex with an
aliquot of the CD25 K/O Kit225 STAT5 cell line,
wherein the IL-2 analog is selected from the group consisting of IL-2 Mutant A (Pegylated βγ-biased IL-2), IL-2 Mutant B (βγ-biased IL-2), and IL-2 Mutant C (Pegylated aldesleukin),
Incubating the cultures for 5 or 6 hours to enable expression of the luciferase
over time,
And measuring expression of the luciferase.
does not reasonably provide enablement for using any cell line, using any Stat5 response element comprising on or more copies of the nucleotide sequence TCCNNNGAA, using any STAT5 responsive reporter system, using any IL-2 analog, and incubating the culture for an indefinite amount of time to enable expression of the luciferase.
The Specification does not enable any person skill 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. The claims, when given the broadest possible interpretation, encompass a method of expressing a peptide in an immune cell, comprising (i) introducing RNA encoding the peptide into the immune cell, and (ii) providing a Toscana virus NSs protein to the immune cell. 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.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the patent coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is not based on a single factor but is rather a conclusion reached by weighing many factors (See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter, 1986) and In re Wands, 8USPQ2d 1400 (Fed. Cir. 1988); these factors include the following:
Nature of invention. The invention encompasses a method for determining the potency of
an IL-2 analog biased for IL-2Rβγ complex over the IL-2Rαβγ complex, comprising:
Providing (i) a cell line that expresses an IL-2Rβγ complex without expression of an IL-2Rαβγ
complex, a STAT5 response element withina promoter linked to an open reading frame encoding a detectable polypeptide, and (ii) serial dilutions of an IL-2 analog biased for IL-2Rβγ complex,
Contacting each serial dilution of the IL-2 analog biased for the IL-2Rβγ complex with an
aliquot of the cell line,
Incubating the cultures for 6 hours to enable expression of the luciferase
over time, and
And measuring expression of the detectably polypeptide to determine the potency of the IL-
2 analog.
Scope of the invention. The invention encompasses a method for measuring the biological
activity of IL-2 mutants with biased activity for the IL-2Rβγ complex.
Number of working examples and guidance. In the instant case, Applicant provides two
relevant working examples. In Example 1, the as-Filed Specification teaches the generation of the Kit225 Stat5-Luc Stable cell line (1.2) and the generation of the CD25 K/o Kit225 Stat5-Luc cell line (1.3). The cells were engineered with a Stat5 response element comprised by Seq ID No:1, and is operably linked to a mini promoter comprised by Seq ID No: 3, which drives expression of an ORF encoding a luciferase peptide as comprised by Seq ID No: 2 (Paragraph [0147]). The example does not teach the use of any other Stat5 response elements, or the use of a Stat5 response element comprising one or more copies of the nucleotide sequence TCCNNNGAA.
Further, the as-Filed the IL-2 Cell Based Reporter assay, wherein IL-2 Mutant A, IL-2 Mutant B, and IL-2 Mutant C are used (Paragraph [150] and Figures 2G, and 2H). There are no other analogs of IL-2 that are being taught in the as-Filed Specification.
Additionally, the as-Filed Specification teaches that the IL-2 Cell based receptor assay was optimized, specifically the treatment time (Paragraph [0156]). The 5, 6, and 7 hour treatment times were tested, wherein the longer treatment time increases the assay window, and the 6 hour treatment time was chosen due to better accuracy, and more practical handling time for the analyst (Paragraph [0156]). Thus, six hours appears to be the optimal time for incubating the cultures before determining the expression of the IL-2 analogs.
State of the art. Although the field of determining the potency of analogs in well known in
the art, the method of determining the potency of IL-2 analogs biased for IL-2Rβγ complex over the IL-2Rαβγ complex, and using a Kit225 cell line that comprises a STAT5 response element, and a promoter linked to an open reading frame encoding a detectable polypeptide is not highly developed.
Unpredictability of the art. Before the effective filing date of the claimed invention, it was
known in the art that the biological activities of IL-2 can be modulated, such that the IL-2-R38A-F42pAF with a 20K 2-branch PEG molecule blocks the binding to IL-2Rα, as evidenced by Chen et al. (WO2020056066 A1, published March 19, 2020) (Paragraph [533]). Additionally, Chen et al. teaches that increasing expression of non-natural amino acid-containing proteins (such as IL-2 variants) in the industry has been challenged by the relative low yield in mammalian cells (Paragraph [526]). This reference shows that the specific IL-2 variant (IL-2-R38A-F42pAF) is biased against the IL-2Rα complex. (Please note: Chen et al. has been listed in the IDS filed April 18, 2025).
Additionally an isolated and modified interleukin 2 (IL-2) polypeptide comprising at least one unnatural amino acid at a position on the polypeptide that reduces binding between the modified IL-2 polypeptide and interleukin 2 receptor α (IL-2Rα) but retains significant binding with interleukin 2 βγ receptor (IL-2Rβγ) signaling complex to form an IL-2/IL-2Rβγ complex was known in the art, wherein the unnatural amino acid is selected from Seq ID No: 1, as evidenced by Ptacin et al. (US 20210070827 A1, published March 11, 2021). (Paragraph [0465]). This reference also teaches the use of particular IL-2 variants that have specific binding affinities. (Please note: Ptacin et al. has been listed in the IDS filed April 18, 2025).
Furthermore, it is known in the art that IL-2 analogs can have from about 1 to about 50 amino acid substitutions, or any integer in between, e.g., 25,20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, as evidenced by Austin et al. (US 20020041865 A1, published April 11, 2002) (Paragraph [0073]). Additionally, Austin et al. teaches several analogs are known in the art, including an IL-2 molecule that lacks the initial N-terminal alanine of the native molecule and wherein the cysteine normally present at position 125 is substituted with a neutral amino acid such as serine or alanine (Paragraph [0073]). Thus, this reference this the unpredictability in the art pertaining to the variability in the known IL-2 analogs.
Amount of Experimentation Required. Given the unpredictability of the art, the variability
in the IL-2 analogs known in the art, the low yield of IL-2 variants comprising non-natural amino acids in mammalian cells, and the variability of the cell lines used, the skilled artisan would have to conduct undue, and unpredictable experimentation to practice the claimed invention using the IL-2 analogs and the cell line a cell line that expresses an IL-2Rβγ complex without expression of an IL-2Rαβγ. Furthermore, due to the lack of specific guidance of how to make the IL-2 analogs, it would require undue experimentation to practice the breadth of the instant methods as claimed.
Conclusion
Claims 1 – 4, 29 – 32, and 46 – 54 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VYOMA SHAILESH THAKKER whose telephone number is (571)272-2954. The examiner can normally be reached M-F 8:30 - 5:30 EST.
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/VYOMA SHUBHAM TIWARI/ Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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