DETAILED ACTION
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 .
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on September 4, 2025 is acknowledged. Claims 1-6, 21, 22, 26, and 44 are pending and under review. Applicant has elected SEQ ID NO: 44 from Species Group A and SEQ ID NO: 44 for R1-R72, Arg for zzz and 1 for x from Species Group B, which read on claims 1-7, 9-11, 21-22, 26, 35 and 44.
Claims 7, 9-11, and 35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on December 3, 2024.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
In the instant specification, page 242, line 29 and page 250, line 15 contain hyperlinks. To overcome this objection, applicant may remove the “https:”.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-6, 21, 22, 26 and 44 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.
Regarding Claims 1, 6, and 21 , the phrase "e. g." renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding Claims 3 and 22, MPEP 2173.05(s) states "Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted)." Claims 3 and 22 recite the limitation “DNA sequence listed in Table 1”. Each DNA sequence has a corresponding SEQ ID NO: and may be recited in the claim limitation.
Regarding Claim 22, Claim 1 recites a method with steps for providing a mammalian host cel, maintaining the mammalian cell, purifying the TREM, and formulating the purified TREM. Claim 22 recites an additional product limitation of “an RNA sequence” but does not describe in which step the limitation is applied. The RNA sequence could be part of the TREM, inherent to the mammalian cell, or perform another function. Therefore, the limitations of Claim 22 applied to Claim 1 are indefinite and not clear.
Those claims included in the statement of rejection but not otherwise discussed are rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
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, 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 1, 5, 6, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Kelly, N., et. al., Journal of Virology, Vol. 77, No. 16, p. 8695-9701, published August 15, 2003; Kothe, U., et. al., Analytical Biochemistry, Vol. 356, p. 148-150, published September 1, 2006; and Pappalardo, J., et. al., WO 2104/055941 A2, published April 10, 2014.
Regarding Claim 1, the instant specification defines a “TREM” as “an RNA molecule comprising a structure or property from (a)-(v) below, and which is a recombinant TREM, a synthetic TREM, or a TREM expressed from a heterologous cell” (p. 112, lines 19-21). Property (g) is “(g) a tertiary structure, e.g., an L-shaped tertiary structure” (p. 116, line 30). Therefore, a “TREM” is interpreted as a RNA with a tertiary structure and includes tRNA.
Regarding “purifying the TREM … e.g., according to a method described herein”, for compact prosecution, Claim 1 is interpreted to purifying the TREM according to a method described in the instant specification. The instant specification describes in one embodiment, “a TREM composition is purified by liquid chromatography” (p. 244, TREM purification). Therefore, Claim 1 is interpreted to be purifying the TREM from the mammalian host cell by liquid chromatography.
Kelly teaches a method of providing a mammalian host cell comprising an exogenous nucleic acid expressing tRNAPhe, which is a RNA with a tertiary structure: “we transfected HeLa H1 cells with pU6PheWt” (p. 8696, col. 2). Kelly teaches the cells were maintained under conditions sufficient to express the TREM (p. 8697, col. 1): “Northern blot analysis of the two mutant tRNAs and wild-type yeast tRNAPhe revealed that the three tRNAs were expressed”.
Kelly does not teach purifying the tRNA from the mammalian host cell and formulating the purified TREM as a pharmaceutical composition.
Kothe teaches a method of purifying specific tRNA from cells: “we describe a method for purification of individual tRNAs” (p. 148, col. 1). Kothe teaches their “method is suitable for all tRNAs” (p. 148, col. 1). Kothe teaches purification with “chromatography on reversed-phase HPLC”, which is liquid chromatography (p. 149, col. 1).
Pappalardo teaches a method of formulating tRNA into a pharmaceutical composition: “the present disclosure also relates to pharmaceutical compositions”; “The present disclosure relates to the regulation of the immune system through targeted delivery of the disclosed compounds and an active substance, such as immunomodulators … Examples of immunomodulators include, but are not limited to … tRNA” (p. 9, [0042-043]).
It would have been obvious to one skilled in the art to combine the steps of Kelly, Kothe and Pappalardo to create a method of making a purified tRNA pharmaceutical composition comprising of providing a mammalian host cell comprising an exogenous nucleic acid encoding the tRNA and maintaining the mammalian cell under conditions sufficient to express the TREM, taught by Kelly; purifying the tRNA from the mammalian host cell by liquid chromatography, taught by Kothe; and formulating the purified tRNA as a pharmaceutical composition, taught by Pappalardo because each step can be performed independent and in sequence. The results would be predictable because the method of plasmid cell expression in Kelly are well known and was successful, Kothe teaches their method works for all tRNAs, and Pappalardo allows for tRNA pharmaceutical formulation. Therefore, Claim 1 is obvious over Kelly, Kothe and Pappalardo.
Regarding Claim 5, Kelly teaches their method in a human cell-line, HeLa. Therefore, Claim 5 is obvious over Kelly, Kothe and Pappalardo.
Regarding Claim 6, Kelly, Kothe and Pappalardo teach Claim 1, including Kothe teaching the method of purification.
Kothe teaches a method of purification by removing cell debris, “an aliquot of the reaction mixture by trichloroacetic acid (TCA) precipitation, filtration through a nitrocellulose filter (Sartorius), and scintillation counting in Quickszint 361 cocktail (Zinsser Analytic). Potassium acetate (pH 4.5) was added to the reaction mixture to a final concentration of 0.3 M, followed by extraction with an equal volume of water-saturated phenol to remove proteins. The aa-tRNA was precipitated from the aqueous phase with 2.5 volumes of cold ethanol, and the pellet of aa-tRNA was dissolved in 0.1 M sodium acetate” (p. 148, col. 2); and separating the specific tRNA from other species by chromatography (p. 149, col. 1).
Regarding Claim 22, Claim 22 is rejected under 35 USC 112(b) for indefinite limitations. For compact prosecution, Claim 22 is interpreted as “the method of claim 1, wherein the mammalian host cell comprises an RNA sequence at least 80% identical to an RNA sequence encoded by SEQ ID NO: 44”.
Claim 1 is obvious over Kelly, Kothe, and Pappalardo.
Kelly does not directly teach SEQ ID NO: 44, the DNA sequence of tRNA-Arg in humans. Kelly teaches a method in HeLa cells, a human cell.
SEQ ID NO: 44 has 100% alignment with Accession X53365.1, dated September 9, 2004, GenBank from positions 2115-2202, which is annotated as tRNA-Arg expressed in humans.
Regarding Claim 22, it would have been obvious to one skilled in the art before the effective filing date to use the teachings of Kelly, Kothe, and Pappalardo to create the method of Claim 1 in HeLa cells, which are human cells. GenBank teaches that human cells express the RNA encoded in SEQ ID NO: 44 as tRNA-Arg, and therefore it is inherent to the cells taught by Kelly to comprise an RNA sequence encoded by the DNA sequence of SEQ ID NO: 44. Therefore, Claim 22 is obvious over Kelly, Kothe and Pappalardo.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Kelly, N., et. al., Journal of Virology, Vol. 77, No. 16, p. 8695-9701, published August 15, 2003; Kothe, U., et. al., Analytical Biochemistry, Vol. 356, p. 148-150, published September 1, 2006; and Pappalardo, J., et. al., WO 2104/055941 A2, published April 10, 2014 in further view of Wittig, B. and Wittig S., Nucleic Acids Research, Vol. 5, No. 5, published April, 1978.
Regarding Claim 2, Claim 1 is obvious over Kelly, Kothe and Pappalardo.
Kelly does not teach reverse transcription.
Wittig teaches a method for reverse transcription of tRNA molecules: “In this paper we present evidence that this DNA polymerase fragment also transcribes oligo{A)-tRNA into complementary DNA” (p. 1166, lines 2-3).
It would be obvious to one skilled in the art to combine the teachings of Kelly, Kothe and Pappalardo to create the method of Claim 1 and to further combine the teachings of Wittig to create an exogenous nucleic acid which comprises a RNA, which upon reverse transcription, results in a DNA which can be transcribed into a tRNA, a TREM. It would be predictable to one skilled in the art because Wittig successful reverse transcribes a tRNA into complementary DNA, and Kelly uses a tRNA in their method. Therefore, Claim 2 is obvious over Kelly, Kothe and Pappalardo in further view of Wittig.
Claim 3, 4, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Kelly, N., et. al., Journal of Virology, Vol. 77, No. 16, p. 8695-9701, published August 15, 2003; Kothe, U., et. al., Analytical Biochemistry, Vol. 356, p. 148-150, published September 1, 2006; and Pappalardo, J., et. al., WO 2104/055941 A2, published April 10, 2014 in further view of GenBank entry Accession X53365.1 dated September 9, 2004.
Regarding Claim 3, Claim 1 is obvious over Kelly, Kothe, and Pappalardo.
Kelly, Kothe, and Pappalardo do not teach SEQ ID NO: 44.
GenBank teaches the sequence of tRNA-Arg in Accession X53365.1 which has 100% alignment to SEQ ID NO: 44 from positions 2115-2202, which is annotated as tRNA-Arg expressed in humans.
It would have been obvious to one skilled in the art to have substituted the sequence taught by GenBank into the plasmid taught by Kelly to create an exogenous nucleic acid comprising an RNA sequence at least 90% identical to an RNA sequence encoded by the DNA sequence of SEQ ID NO: 44 because Kelly and GenBank both teach tRNA sequences, which may be substituted as they perform similar functions which are known in the art. One skilled in the art could have substituted one known element for each other and the results would be predictable because Kelly teaches cell expression of several exogenous tRNA with success. Therefore, Claim 3 is obvious over Kelly, Kothe, Pappalardo and GenBank.
Regarding Claim 4, applicant has elected SEQ ID NO: 44 for the consensus sequence, which is the sequence for tRNA-Arg taught by GenBank. Therefore, Claim 4 is obvious over Kelly, Kothe, Pappalardo and GenBank.
Regarding Claim 26, applicant has elected SEQ ID NO: 44, which is the sequence for tRNA-Arg.
Claim 1 is obvious over Kelly, Kothe, and Pappalardo.
Kelly, Kothe, and Pappalardo do not teach SEQ ID NO: 44.
GenBank teaches the sequence of tRNA-Arg in Accession X53365.1 which has 100% alignment to SEQ ID NO: 44 from positions 2115-2202, which is annotated as tRNA-Arg expressed in humans.
It would have been obvious to one skilled in the art to have substituted the sequence taught by GenBank into the plasmid taught by Kelly to create TREM pharmaceutical composition comprising of SEQ ID NO: 44 because Kelly and GenBank both teach tRNA sequences, which may be substituted as they perform similar functions which are known in the art. One skilled in the art could have substituted one known element for each other and the results would be predictable because Kelly teaches cell expression of several exogenous tRNA with success. Therefore, Claim 26 is obvious over Kelly, Kothe, Pappalardo and GenBank.
Claims 21 and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Kelly, N., et. al., Journal of Virology, Vol. 77, No. 16, p. 8695-9701, published August 15, 2003; Kothe, U., et. al., Analytical Biochemistry, Vol. 356, p. 148-150, published September 1, 2006; and Pappalardo, J., et. al., WO 2104/055941 A2, published April 10, 2014 as applied to Claim 1 above, and further in view of Bracewell, D. et. al., Biotechnology and Bioengineering, Vol. 112, No. 9, published July 14, 2015; Capece, M. et. al., RNA, Vol. 21, No. 2, p. 296-305, published Feb 2015; USP, 34(6) Sixth Interim Revision Announcement: 71, Sterility Tests, dated Nov. 21, 2016.
Regarding Claim 21, Kelly, Kothe, and Pappalardo teach Claim 1.
Kelly, Kothe, and Pappalardo do not teach providing a value for one or more of HCP contamination, in-vitro translation activity, sterility and viral contamination.
Bracewell teaches a method of providing or acquiring a value for HCPs through ELISA or mass spectrometry and “ [t]hese techniques can potentially both identify and quantify HCP” (p. 1727, Abstract). Bracewell also teaches, “The “traditional” practice is to set a target of 100 ng/mg” (p. 1732, col. 1), but impurities should be kept to “lowest reasonable level of residual HCP” (p. 1732, col. 2). Therefore, Bracewell teaches HCP 100 ng/mg or less.
Capece teaches a method of providing or acquiring a value for in vitro translation activity: “The SNAP assay enables quantitative, real-time measurement of overall translation rates in vitro via the synthesis of O6 -alkylguanine DNA O6 -alkyltransferase (SNAP)” (p. 1, Abstract).
USP teaches a method of providing or acquiring a value for sterility of liquids by introduction into culture media (p. 9, Direct Inoculation of the Culture Media). The sterility is measured by microbial growth in the culture media: “If no evidence of microbial growth is found, the product to be examined complies with the test for sterility” (p. 11).
It would be obvious to one skilled in the art before the effective filing date to combine the teachings of Kelly, Kothe, and Pappalardo to create the method of Claim 1 and to further combine the teachings of Bracewell, Capece and USP to provide a value for the HCP contamination less than 100ng/mg, in-vitro translation activity and sterility. One skilled in the art could combine these methods because each step is sequential and independent. The results would be predictable because Bracewell describes their practice as traditional, Capece provides evidence their method measures in vitro activity, and USP is document that provides GMP guidelines. Therefore, Claim 21 is obvious over Kelly, Kothe, Pappalardo, Bracewell, Capece and USP.
Regarding Claim 44, It would be obvious to one skilled in the art before the effective filing date to combine the teachings of Kelly, Kothe, and Pappalardo to create the method of Claim 1 and to further combine the teachings of Bracewell, Capece and USP to acquire a value for the HCP contamination less than 100ng/mg, in-vitro translation activity and sterility. One skilled in the art could combine these methods because each step is sequential and independent. The results would be predictable because Bracewell describes their practice as traditional, Capece provides evidence their method measures in vitro activity, and USP is document that provides GMP guidelines. Therefore, Claim 21 is obvious over Kelly, Kothe, Pappalardo, Bracewell, Capece and USP.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Krishna Nuggehalli Ravindra whose telephone number is (571)272-2758. The examiner can normally be reached M-Th, alternate F, 8a-5p est.
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/K.N.R./Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636