DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Applicant’s amendment and response filed on 7/22/2026 has been received and entered into the case.
Claims 1-21, 23-28, 33-38, 40-42, 47-53, 55-57 have been canceled, claims 68-70 are newly added, and claims 22, 29-32, 39, 43-46, 54, 58-70 have been considered on the merits. All arguments have been considered.
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 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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 22, 29-32, 39, 43-46, 54 and 58-67 is/are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Guild et al. (of record) in view of Halenbeck et al. (US 2008/0286834; IDS ref.).
Regarding claim 22, Guild teaches methods of treatment of diseases by delivery of compositions that transfect target cells (para. 6), wherein the composition comprises mRNA (para. 8) and comprise an mRNA and a transfer vehicle (para. 9). Guild teaches that the nucleic acids can be formulated in a lipid or liposome transfer vehicle, or can be a lipid nanoparticle (para. 11).
Guild do not explicitly teach that the mRNA encodes a protein that is not normally secreted by a cell, operably linked to a secretory leader sequence that is capable of directing secretion of the encoded protein as recited in claim 22.
However, Halenbeck teaches methods for producing proteins in higher yields by replacing the endogenous secretory leader sequence with a heterologous secretory leader sequence, or by adding a heterologous secretory leader sequence to a protein that would not contain a leader sequence (para. 8). Halenbeck teaches that the proteins are expressed from sequences that encode their full-length amino acid sequences (para. 56). Halenbeck teaches that various secretory leader sequences that can be used to express a wide variety of polypeptides (paras. 92-93). Halenbeck teaches that their methods would be useful for therapeutic applications (para. 7).
Accordingly, given that Guild teaches that their methods of treatment would be used to secrete a functional protein from a target cell (see para. 12; p. 20, claim 95) and Halenbeck teaches that their methods of using a secretory leader sequence produces higher yields of secreted proteins that would be used for therapeutic purposes, it would have been obvious to the skilled artisan to modify Guild’s teachings to include a secretory leader sequence, as taught by Halenbeck, for the purposes of producing higher yields of secreted proteins. One of skill in the art would have had a reasonable expectation of success in the modification because Halenbeck teaches that their modifications result in higher levels of protein expression.
Regarding the limitation directed to the intramuscular administration (claim 22), Guild teaches suitable routes of administration includes intramuscular injection (para. 93).
Regarding claim 29, Guild teaches that the transfer vehicle facilitates delivery to target cells (para. 11) to transfect the mRNA intracellularly (para. 49).
Regarding claim 30, Guild teaches that cationic lipids may be used with lipid nanoparticles (para. 60).
Regarding claim 31, Guild teaches the use of non-cationic lipids with a lipid nanoparticle (paras. 62-63).
Regarding claim 32, Guild teaches that PEG can be used to modify the lipid nanoparticle (para. 61).
Regarding claims 39 and 66-67, Guild teaches that the target cells can comprise hepatocytes, epithelial cells, skeletal muscle cells, lung cells, bone cells, etc. (para. 79). The teaching of lung cells would meet the limitation of claim 67, and skeletal muscle cells would meet the limitation of claim 66.
Regarding claim 43, Guild teaches that the mRNA comprises a modification that confers stability (paras. 10; p.19, claim 3).
Regarding claim 46, Guild teaches the composition comprising mRNA and a transfer vehicle further comprising an agent for facilitating transfer of the RNA molecules to an intracellular compartment of the target cell (para. 73; p.19, claim 15).
Regarding claim 54 directed to the dose ranging 30-200 mg of mRNA, Guild teaches 200 mg of encapsulated mRNA (para. 120).
Regarding claims 58-63 directed to the polypeptide being detectable in a body fluid of the subject for more than 4, 6, 12, 24, 48 or 72 hours after intramuscular administration, these limitations are directed to the results rather than requiring any additional active step to be carried out for the claimed method of claim 22. Thus, the wherein clause of these claims does not provide patentable weight. Furthermore, as the method taught by Guild is identical to claim 1, and thus, the results are expected the same.
Regarding claims 64 and 65 directed to the 5’-UTR having SEQ ID NO:1 and the 3’-UTR having SEQ ID NO:2, Guild teaches 5’ CMV sequence (SEQ ID NO:2) and 3’ hGH sequence (SEQ ID NO:3), and they are 100% identical to SEQ ID NO:1 of claim 64, and SEQ ID NO:2 of claim 65, respectively.
Thus, the claimed invention, as a whole, is clearly prima facie obvious in the absence of evidence to the contrary.
Claims 68-70 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Guild et al. in view of Halenbeck et al. as applied to claim 67 above, and further in view of Kariko et al. (WO2011/071931A2).
Regarding claims 68-70 directed to the administering step of claim 67 being to the lungs of the subject, intratracheally administered or being inhaled, the cited references do not teach the limitation. However, as the combined teachings of Guild et al. in view of Halenbeck et al. disclose the administering the composition to the target cells including lung cells (para. 13 of Guild et al.), and the target tissue being lungs (para. 71 of Guild et al.), it would have been obvious to a person skilled in the art to utilize a known delivery system for lung cells in the lungs.
It is extremely well known in the art that a composition comprising mRNA targeting lung cells in the lung would be delivered via intratracheal administration including using an inhaler or inhalation according to Kariko et al. (p.105, Example 18; p.114, lines 3-5; Example 24).
It would have been obvious to a person skilled in the art to use intratracheal injection or inhalation using an inhaler taught by Kariko et al. with a reasonable expectation of success because these routes are well known for the delivery of mRNA into the lung or lung cells therein.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Arguments
Applicant's arguments filed 7/22/2026 have been fully considered but they are not persuasive.
Regarding the 112(a) rejection, the instant amendment (cancellation) of claims 47-53 overcame the rejection, and thus, the rejection has been withdrawn.
Regarding the 103 rejection, applicant stated that the post-filing evidence demonstrates the surprising and unexpected discovery that mRNA constructs encoding a protein that is not normally secreted by a cell and linked to a heterologous secretory leader sequence are capable of expressing and secreting the encoded protein of interest compared to similar mRNA constructs that do not contain a heterologous secretory leader sequence. See, e.g., W02023214082, at Example 3 which demonstrates that adding the secretion signal (HA-SS) to an mRNA construct encoding the OspA antigen induced antibody titer. The induction of antibody expression in this context is only possible if the encoded protein is expressed and secreted. Thus, the Exhibit A data of antibody titer is a proxy for the claimed method. Accordingly, post-filing date evidence establishes the surprising and unexpected discovery that the claimed mRNA constructs are capable of expressing and secreting a protein that is not normally secreted by a cell.
The Examiner does not agree with this allegation. It is the Examiner’s position that the effect shown by the Exhibit A is limited to the mRNA encoding OspA, and this cannot be applicable any non-secretory protein without any evidence. The scope of the claimed method encompasses any non-secretory protein, and applicant alleges that in the presence of signal sequence for any of those non-secretory protein, the expression level would be increased. First, there is no evidence that the effect alleged by the Exhibit A would be universal to any non-secretory protein. Second, the hemagglutinin signal sequence utilized by the Exhibit A would not represent the entire signal sequences contemplated by the instant claims and/or HEK293 cells for any cells of the subject in vivo including lung cells as claimed.
As discussed in the previous OA, even if there is unexpected results of using hemagglutinin signal sequence in expression of a viral protein (OspA), however, there is no evidence the alleged “unexpected results” would be the same case for any non-secretory protein expressed in any endogenous mammalian cells.
Furthermore, as Halenbeck et al. teach, adding a heterologous secretory leader sequence to a protein that would not contain a leader sequence produces proteins in higher yield (para. 8). This teaching indicates that one skilled in the art would expect that the additional of secretory leader sequence or signal sequence would increase production of non-secretory proteins.
Applicant argued that Halenbeck focuses on increasing the production of proteins that are naturally secreted by cells and does not teach or disclose for producing proteins that are not normally secreted by a cell. As discussed above, Halenbeck et al. teach adding a heterologous secretory leader sequence to a protein that would otherwise not contain a leader sequence (para. 8). This teaching is contrary to the applicant’s assertion.
Based on the above discussion, it is the Examiner’s position that the combined teachings of Guild and Halenbeck render the claimed invention obvious.
Thus, in the absence of clear evidence and the teaching of Halenbeck et al., it is the Examiner’s position that the alleged “unexpected” or “surprising” results is not persuasive, and the combined teachings of the cited references render the claimed invention obvious.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 TAEYOON KIM whose telephone number is (571)272-9041. The examiner can normally be reached 9-5 EST Monday-Friday.
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/TAEYOON KIM/Primary Examiner, Art Unit 1631
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