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 . Applicant’s amendment filed 5/18/2026 is acknowledged. Claim 17 has been amended. Claims 1-17 are pending. All of the amendment and arguments have been thoroughly reviewed and considered. Any rejection not reiterated in this action has been withdrawn as being obviated by the amendment of the claims.
This action is made Final.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Previous rejection
The prior art rejection under 35 USC 103 directed to the claims 1-17 as being unpatentable over Beverly in view of Marquardt et al is maintained and discussed below.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1-17 is/are finally rejected under 35 U.S.C. 103 as being unpatentable over Beverly et al (US 20200325532, October 15, 2020) in view of Marquardt et al (20180274009, September 2018, effective filing date October 2016)
Regarding claim 1, Beverly et al teach a method of determining a mRNA poly(A) tail size comprising: digesting an mRNA molecule to liberate a poly(A) tail; preparing a chromatographic sample comprising the mRNA poly(A) tails; preparing a second chromatographic sample comprising a reference sequence with a predetermined length; separating the first and second samples by a chromatography method, which result in one or more chromatograms; and determining a sequence length of the mRNA poly(A) tails by comparing the chromatograms of the first and second samples (see entire document, especially paragraphs [0008] – [0013], [0017] – [0019], [0024] –[0025], [0043], [00113] – [0114], [0123], [0125] – [0126], [0152] – [0171]; see also paragraphs [0174] – [0177] which teaches mass spectrometry techniques performed to carry out the method).
Regarding claims 2 and 11, Beverly teaches wherein the reference sequence comprises 30-150 nt in length ([0125]-[0126] and [0152] – [0171]).
Regarding claims 3 and 5, Beverly teaches further comprising selecting a length of the reference sequence by calibrating with a DNA or RNA reference sequence standard (see [0040] – [0043], [0125] –[0173]).
Regarding claim 4, Beverly teaches that the mRNAs can be produced synthetically through in vitro transcription. In vitro, MRNAs gain their polyA tails either by encoding the polyA sequence into the template DNA or by having he polyAs added post-synthesis using a polyadenylase ([0054]).
Regarding claim 6, Beverly teaches wherein the mRNA poly(A) tails range between about 80 to about 120 oligonucleotides ([0100], [0109]).
Regarding Claim 7, Beverly teaches wherein the mRNA poly(A) tails have a length distribution that is observable from chromatogram having high resolution ([0047] – [0048], [0057]. [0099], [0208], [0210], Table 1).
Regarding claim 8, Beverly teaches wherein the method further comprises calculating the dispersity of the mRNA poly(A) tails based on one or more poly(A) tail peak widths of the chromatograms ([0044], [0046] – [0048], [0201], Table 1 and [0215]).
Regarding claim 9, Beverly teaches wherein the chromatography method is performed with mass spectrometry (MS) compatible mobile phases ([0068], [0071], [0200]).
Regarding claim 10, Beverly teaches wherein the digesting step comprises liberating the 3' poly(A) tail of the mRNA molecule by enzymatic cleavage [0108].
Regarding claims 12-17, Beverly teaches wherein the chromatography method may comprise of ultraviolet ion-pair reversed- phase liquid chromatography (IP RP LC UV) ([0208]).
Beverly differs from the instant invention in that Beverly does not expressly teach the order of method steps recited therein. However, MPEP2144.04 states that the selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930).
Beverly does not expressly teach the use of a combination of different chromatograph assay as recited by the instant claims.
Regarding claims 1-17, Marquardt et al teach a method comprising: (a) digesting a test mRNA with an RNase enzyme to produce a plurality of mRNA fragments; (b) physically separating the plurality of mRNA fragments; (c) determining the masses of the fragments; (d) identifying the test mRNA by comparing the signature to the predicted mass pattern (e.g., a theoretical pattern) and/or an empirically-derived chromatographic pattern, and (e) confirming the identity of the test mRNA if the observed masses and/or chromatogram [0009].
At paragraph [0013] and [0014]. Marquardt et al teach in some embodiments, the physical separation and/or the detecting is achieved by one or more methods selected from the group consisting of: gel electrophoresis, liquid chromatograph, high pressure liquid chromatography (HPLC), and mass spectrometry. In some embodiments, the HPLC is HPLC-UV. In some embodiments, the mass spectrometry is Electrospray Ionization mass spectrometry (ESI-MS) or Matrix-assisted Laser Desorption/Ionization mass spectrometry (MALDI).
[0014] In some embodiments, the signature assigned to the test mRNA is an absorbance spectrum, a mass spectrum, a UV chromatogram, a total ion chromatogram, an extracted ion chromatogram, a combination of extracted ion chromatograms, or any combination of the foregoing.
Marquardt et al teach at paragraph [0055], [0078], [0083], that the Figures 13, 37, and 42, respectively, depict data for mRNA tail length determination by reverse-phased ion paired chromatography with UV detection or by liquid chromatography-mass spectrometry (LC-MS). See also paragraphs [0183], [0184], [0189], [0203] and [0208] – [0210] which further discuss determining poly-A tail length identification and quantification using chromatographic techniques.
Marquardt further teaches that test mRNA can be physically separate by chromatography or mass spectrometry. The reference teaches examples of chromatography within the scope of the invention comprise size exclusion chromatography, high performance liquid chromatography ad mass spectrometry techniques comprise electrospray ionization mass-spectrometry, matrix-assist laser desorption ionization mass spectrometry and further may encompass various combinations thereof ([0157]). Marquardt teaches that coupling various techniques allow for second dimension of separation as well as detection [0157].
It would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date of the claimed invention to have been motivated to have combined the teachings of Beverly with the teachings of Marquardt since they are of similar scope and both are directed to method steps involved in measuring mRNA poly-A tail lengths using chromatogram data. The ordinary artisan would have been motivated to utilized and/or combined different types of chromatography techniques in the method of Beverly and Marquardt for the benefit of providing multiple dimensions of separations thereby increasing specificity and sensitivity of determining mRNA poly(a) tail lengths as suggested by Marquardt. The combination of the cited prior art is prima facie obvious in the absence of secondary consideration.
Response to Arguments
Applicant’s traversal
Applicant traverses the rejection on the following grounds: Applicant summarizes the claimed invention and cited prior art and respectfully disagree with the Examiner’s assertion.
(a) Applicant states that Beverly fails to teach or suggest Applicant’s required step of “determining a sequence length of the mRNA poly(A) tails by comparing the chromatograms of the first and second samples.
(b) Applicant states that Beverly is directed to method of analyzing composition of RNA (e.g., mRNA), suitable for use as therapeutic or making a therapeutic, using mass spectrometer. Applicant state Beverly exclusively determines the lengths of mRNA molecules using mass spec and cites para. [0058].
(c) Applicant states at no point does Beverly teach or suggest that any information can ascertained from analysis of MRNA without mass spectrometry nor do Beverly teach or even suggest that sequence length of the mRNA poly(A) tails can be determined through chromatograms. Applicant cites para. [0057] and [0058].
(d) Applicant states that while Beverly does describe that a reference value may be obtained, Beverly makes clear that this value is not used in determining the length of the poly(A) tail by comparing chromatograms of the first and second samples but rather a qualitative comparison.
(e) Applicant notes that both Beverly and Marquardt provide methods that use MS data for determination of length not chromatogram data as the Office alleges.
(f) Applicant states Marquardt provides methods that use MS data for the determination of length not chromatograph data as the Office alleges and Marquardt not only also uses MS data for determination pf length not chromatogram data. Applicant cites paragraph Marquardt at paragraphs [0055], [0078] and [0083].
Examiner’s Response
All of the amendment and arguments have been thoroughly reviewed and considered but are not found persuasive of the reasons that follow:
i. Regarding the arguments (a) through (f) above concerning the cited prior art of Beverly in view of Marquardt, the examiner acknowledges applicant’s arguments but respectfully disagree. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Specifically, in response to Applicant’s arguments that the teachings of Beverly only focus on analysis of MRNA using mass spectrometry and not using chromatogram, the examiner respectfully disagree because Beverly teaches e.g., liquid chromatography coupled to electrospray mass spectrometry (LC-MS) or matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), to determine the polyA species present in the RNA composition ([para. 0004]) and providing a relative distribution of poly(A) chain length(s) or an amount of a poly(A) chain length from isolated polyA tails from the RNA in the RNA sample, by mass spectrometry, e.g., LC-MS or MALDI-MS, to provide a test value; (c) providing a determination of whether the test value is an amount or has a relative distribution of a reference value; and (d) further processing the RNA composition based upon the determination. At para. [0044], Beverly discloses that Figure 1 is a set of chromatograms showing LC-MS analysis showing polyA tail lengths. At para. [0047], Beverly discusses three UV250 nm chromatograms from LC-MS analysis of mRNA with polyA tails of different lengths. Still further at paragraph [0057], Beverly teaches that there are many techniques to characterized the polyA tail length of mRNA, such as chromatographic methods and further teaches that chromatography usually show smears for a population of different tail lengths.
The secondary teachings of Marquardt discuss chromatographic patterns and representative quantitative data on mRNA tail length determination by chromatographic techniques (see e.g., Figure 14).
Thus, the combination of the cited prior art provides a prima facie case of obviousness that the determining a sequence length of the mRNA poly(A) tails by comparing chromatograms is within the ordinary artisan’s capabilities given the teaching of the cited prior art. Applicant is reminded that the court commented that "[r]esponding to concerns about uncertainty in the prior art influencing the purported success of the claimed combination, this court [in O'Farrell] stated: '[o]bviousness does not require absolute predictability of success ... all that is required is a reasonable expectation of success."' Kubin, 561 F.3d at 1360 (citing In re O'Farrell, 853 F.2d at 903-904).
In response to Applicant’s arguments that the teachings of Marquardt teaches away from chromatogram analysis, The Courts have noted “[W]hen a piece of prior art ‘suggests that the line of development flowing from the reference's disclosure is unlikely to be productive of the result sought by the applicant’ the piece of prior art is said to ‘teach away’ from the claimed invention. In re Gurley, 27 F.3d 551, 553 (Fed.Cir.1994). As with other subsidiary obviousness inquiries, ‘[w]hat a reference teaches and whether it teaches toward or away from the claimed invention are questions of fact.’ [Winner Intern. Royalty Corp. v. Wang, 202 F.3d 1340, 1349 (Fed. Cir. 2000)] (internal quotations omitted). However, obviousness must be determined in light of all the facts, and there is no rule that a single reference that teaches away will mandate a finding of nonobviousness. Likewise, a given course of action often has simultaneous advantages and disadvantages, and this does not necessarily obviate motivation to combine. See id. at 1349 n. 8 (“The fact that the motivating benefit comes at the expense of another benefit, however, should not nullify its use as a basis to modify the disclosure of one reference with the teachings of another. Instead, the benefits, both lost and gained, should be weighed against one another.”). Where the prior art contains ‘apparently conflicting’ teachings (i.e., where some references teach the combination and others teach away from it) each reference must be considered “for its power to suggest solutions to an artisan of ordinary skill.... consider[ing] the degree to which one reference might accurately discredit another.’ In re Young, 927 F.2d 588, 591 (Fed.Cir.1991).” Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2006) (emphases added).
Finally, MPEP 2123 notes “[D]isclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). “A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use.” In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994) (The invention was directed to an epoxy impregnated fiber-reinforced printed circuit material. The applied prior art reference taught a printed circuit material similar to that of the claims but impregnated with polyester-imide resin instead of epoxy. The reference, however, disclosed that epoxy was known for this use, but that epoxy impregnated circuit boards have “relatively acceptable dimensional stability” and “some degree of flexibility,” but are inferior to circuit boards impregnated with polyester-imide resins. The court upheld the rejection concluding that applicant’s argument that the reference teaches away from using epoxy was insufficient to overcome the rejection since “Gurley asserted no discovery beyond what was known in the art.” Id. at 554, 31 USPQ2d at 1132.). Furthermore, “[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).”
Applicant’s arguments are not found persuasive to obviate the rejections of the prior Office action. Accordingly, the rejections under 35 USC 103 is maintained.
Conclusion
No claims are allowed. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CYNTHIA B WILDER whose telephone number is (571)272-0791. The examiner can normally be reached Flexible.
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/CYNTHIA B WILDER/Primary Examiner, Art Unit 1681
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