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 .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This Action is in response to the papers filed June 16, 2026 and July 16, 2026.
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 07/16/2026 has been entered.
Claims 44 and 71 have been amended, no claims have been canceled, and claim 81 has been added as set forth in the claim set filed 06/16/2026. Claims 1, 14, and 28 are independent claims.
Therefore, claims 1-2, 14, 19, 23, 28, 31, 36, 44, 55-56, 58-59, 61-62, 68, 71 and 81 are pending in the application and examined on the merits.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2020/044158 filed July 30, 2020
Applicant’s claim for the benefit of a prior-filed parent provisional application 62/880,418 filed 07/30/2019 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is July 30, 2019.
Response to arguments
Withdrawn objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 112(b)
The rejection of claims 44 and 55 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, has been withdrawn.
Applicant’s arguments and amendments filed 06/17/2026 and 07/16/2026 have been considered and are persuasive. In particular, the amendments to correct Markush groupings.
Maintained objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 103
Claim 1, 2, 14, 19, 23, 28, 31, 36, 44, 55, 56, 58, 61, 62, 68, and 71 remain rejected and claim 81 is newly rejected under 35 U.S.C. 103 as being unpatentable over DeRosa (US20180125989; Published 2018-05-10; Applicant’s own work) as evidenced and in view of Alton (2016, National Institute for Health Research; IDS Reference).
Regarding claim 1, DeRosa teaches administering a nucleic acid encoding a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein to a subject in need thereof (Claim 2). The subject can be a human afflicted with or is susceptible to cystic fibrosis (para. 0067, 0076). The nucleic acid is a messenger RNA (mRNA) (Example 1). The aerosol administered to the subject is produced by nebulization of 10mg (i.e. between 7 mg and 25 mg) mRNA of codon optimized CFTR (CO-hCFTR) (Example 3).
Although DeRosa does not explicitly teach that the treatment results in at least a 3% increase in absolute change in ppFEV1 at two days following the administration, as each and every method step and limitation of the treatment is taught by DeRosa, results such as a 3% increase in absolute change in ppFEV1 at two days following the administration are inherently present as a result of the administration of the mRNA encoding CFTR at 10 mg to a subject. However, in the alternative, it would have been prima facie obvious to one of ordinary skill in the art to optimize the parameters of the method at a week in order to achieve the best means for achieving a desired result.
Although DeRosa does not explicitly teach that the treatment results in at least a 2% increase in absolute change in ppFEV1 at one week following the administration, as each and every method step and limitation of the treatment is taught by DeRosa, results such as 2% increase in absolute change in ppFEV1 at one week following the administration would present as a result of the administration of the mRNA encoding CFTR at 10 mg to a subject with a reasonable expectation of success. However, in the alternative, it would have been prima facie obvious to one of ordinary skill in the art to optimize the parameters of the method at a week in order to achieve the best means for achieving a desired result.
Regarding claim 2, DeRosa teaches the composition is nebulized at a dose of 10mg and administered to a subject. DeRosa additionally teaches that 15mg and 30mg were produced by the same method to make the 10mg dosage (para. 0258-0265). Moreover, DeRosa discloses that the composition administered contains at least about 10mg, 100 mg, 500mg and so on of encapsulated mRNA. Although DeRosa does not explicitly state that the dosages are 16, 20 or 24 mg, DeRosa teaches that the present invention can be used to deliver mRNA at various doses with dosages ranging from 0.1-5.0 mg/kg body weight. Therefore, if taking an average human subject into account (80kg) which would be 8mg to 400mg and encompasses the claimed dosages. Thus, to achieve a dosage of 16, 20 or 24 mg administered would be a case of routine optimization.
Regarding independent claims 14 and 28, DeRosa teaches administering a nucleic acid encoding a encoding a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein to a subject in need thereof (Claim 2). The subject can be a human afflicted with or is susceptible to cystic fibrosis (para. 0067, 0076). The nucleic acid is a messenger RNA (mRNA) (Example 1). The aerosol administered to the subject comprise exemplary lipid nanoparticles (LNP) preparations which have a final concentration of 0.5 mg/mL CTFR mRNA which is nebulized for a total of 10mg mRNA of codon optimized CFTR (CO-hCFTR) (para. 0247-0249; Example 3).
However, DeRosa does not teach how long the exposure duration is, and specifically does not teach the duration as at least 30 minutes or 135 minutes or less which results in at least a 3% increase in ppFEV1 and 2% increase in absolute change in ppFEV1 at one week following the administration.
Alton teaches delivering CTFR gene therapy through nebulization for 3 minutes of tidal breathing and then 40 minutes (i.e. less than 135 minutes) which was determined as a period after which delivery was complete (p. 19). Alton teaches that after the treatment, FEV1 showed a 3.7% change (p. 44).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to deliver the CTFR mRNA LNPs of DeRosa for less than 135 minutes with a reasonable expectation of success to achieve at least a 3% improvement in ppFEV1 and 2% increase in absolute change in ppFEV1 at one week following the administration as taught by Alton. An artisan would be motivated to utilize the nebulization for about 40 minutes as Alton teaches that it takes about 40 minutes to complete the delivery of the CTFR gene therapy through nebulization (p. 19). In relation to the recitation of 0.5 mg/ml to 0.8 mg/ml, it would have been prima facie obvious to one of ordinary skill in the art to optimize the parameters of the composition a composition comprising an mRNA encoding a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein in order to achieve the best means for achieving a desired result. As each and every step of the claim is taught by the combination of DeRosa and Alton, the same steps yield the same predictable results with a reasonable expectation of success.
Regarding claim 19, the combined teachings of DeRosa and Alton render obvious claim 14. Although DeRosa and Alton teach nebulization for 3 minutes of tidal breathing and then 40 minutes resulting in a 3.7% FEV1 change (p. 44), the cited references do not explicitly teach that the treatment results in at least a 4% to at least 25% increase in absolute change in ppFEV1 following the treatment period. However, as each and every method step and limitation of the treatment is taught by DeRosa and Alton, results such as a 4% to at least 25% increase in absolute change in ppFEV1 from the baseline following the administration are inherently present as a result of the administration of the mRNA encoding CFTR at 10 mg to a subject. Furthermore, DeRosa details multiple different intervals for dosing (para. 0232). In the alternative, it would have been prima facie obvious to one of ordinary skill in the art to optimize the parameters of the method such as interval dosages at a week in order to achieve the best means for achieving a desired result.
Regarding claim 23, DeRosa and Alton render obvious the method of claim 14. Moreover, DeRosa does teach the timing of the expression of the mRNA expression of CFTR tuned to suit a particular medical need such as being detectable from 1 to 72 hours in serum or tissues or for weeks (para. 0238-0239). Moreover, Alton teaches a method of administering a CTFR polynucleotide to treat cystic fibrosis and measuring pulmonary function 2 days after reach dosing visit via spirometry to measure FEV1 (i.e. ppFEV1) (p. 108, Step 7; p. 112, Day 2 post-dosing visits). Alton teaches that FEV1 in cystic fibrosis is closely linked to survival and is the most widely used primary outcome in clinical trials (p. 24, Spirometry; p. 44).
Regarding claim 31, DeRosa and Alton render obvious the method of claim 28, Moreover, DeRosa teaches that the subject which can be human suffering from or at risk of cystic fibrosis (para. 0076, 0081-82)
Regarding claim 36, DeRosa and Alton render obvious the method of claim 28. Moreover, Alton teaches treating human subjects with cystic fibrosis with F508del mutations as well as other class mutations with CFTR gene therapy (p. 43, Mutation class), falling within the scope of claim 36, (b).
Regarding claims 44 and 55, DeRosa and Alton render obvious the method of claim 28. Moreover, Alton teaches that ppFEV1 is stablished prior to gene therapy which would encompass measurements following prior administration of CFTR modulator therapy.
Alton teaches that a follow-on study should examine dose escalation, frequency of dosing, and the potentially attractive combination of gene therapy with a CFTR potentiator (i.e. ivacaftor) (p. 90, 2nd paragraph; p. xxv, Future Work).
Regarding claim 56, DeRosa and Alton render obvious the method of claim 28. Moreover, Alton teaches treating human subjects with cystic fibrosis with baseline ppFEV1 between about 50% to about 90% of normal (p. 43, Percentage predicted FEV1), reading on the limitations of claim 56.
Regarding claim 58, DeRosa and Alton render obvious the method of claim 28. Moreover, DeRosa teaches a codon optimized human CFTR mRNA sequence under SEQ ID NO: 8 (para. 0208). SEQ ID NO: 8 has a 100% identity to SEQ ID NO: 28 of the present application as evidenced by the RNG results from the sequence search conducted as seen below.
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Regarding claim 61, DeRosa and Alton render obvious the method of claim 28. Moreover, DeRosa teaches that the mRNA is synthetized as either modified or unmodified mRNA (para. 0070).
Regarding claims 62, 68, 71 and 81, DeRosa and Alton render obvious the method of claim 28. Moreover, DeRosa teaches that the mRNA is administered through an aqueous solution nebulized comprising lipid nanoparticles encapsulating the mRNA which have three distinct lipid components: helper lipids, PEG-modified lipids, and cationic lipid (para. 0006-0007, 0084, 0242)
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Claim 59 remains rejected under 35 U.S.C. 103 as being unpatentable over DeRosa (US20180125989; Published 2018-05-10; Applicant’s own work) in view of Alton (2016, National Institute for Health Research; IDS Reference) as applied to claim 28 above, and in further view of Butora (US20190211368; Published 2019-07-11)
As discussed above in the rejection of independent claim 28, DeRosa and Alton teach a method of administering a mRNA encoding a CFTR protein to a subject in need thereof. The aerosol administered to the subject comprise exemplary lipid nanoparticles (LNP) preparations which have a final concentration of 0.5 mg/mL CTFR mRNA which is nebulized for a total of 10mg mRNA of codon optimized CFTR (CO-hCFTR) and administered for a duration of less than 135 minutes as iterated above in the 103 rejection the content of which is incorporated herein, in its entirety.
However, regarding claim 59, DeRosa and Alton do not teach that the mRNA has a 5’ cap with a structure of
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Butora teaches cap analogs which result in high levels of capping efficiency and transcription and improved translation efficiencies (Abstract, para. 0519, Table 1-2, Example 1). As evidenced by the Structure Search on pages 31-32, the structure of the cap analog is the same as the structure claimed in Claim 59.
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to utilize the cap analog of Butora as the 5’ cap of the mRNA of DeRosa with a reasonable expectation of success. An artisan would have been motivated to do so as Butora teaches cap analogs which result in high levels of capping efficiency and transcription and improved translation efficiencies.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
In response to Applicants’ arguments or amendments regarding the above 103 rejections,
Applicants’ arguments and amendments regarding the 103 rejection have been considered, however they are not persuasive.
Applicant argues hindsight reasoning has been utilized to arrive at the claimed invention and that obviousness cannot be predicated on what is unknown. Moreover, Applicant argues that an artisan would not have been able to predict the present invention’s results found in Example 3 as DeRosa only shows reduction to practice in mice and not humans. Applicant argues against the utilization of MPEP 2107.01 as a rationale to support the position that animal testing can inform an artisan of a human therapeutic’s utility as persuasive in an obviousness rejection.
Examiner reiterates the statements from the previous Office Action, that “the reduction to practice involves rodents, however, as previously stated in the above 103 rejection, DeRosa discloses that the subject can be a human with cystic fibrosis. Furthermore, Alton demonstrates improved ppFEV1 results in humans as well. Alton teaches that after the treatment, FEV1 showed a 3.7% change (p. 44). Thus, there is a teaching or suggestion that one would achieve the same results for the increase in ppFEV1 from the same steps with a reasonable expectation of success.” Regarding Applicant refuting MPEP 2107.01, Applicant directly undermines their previous arguments. Applicant states that MPEP sections regarding utility are “irrelevant to an obviousness analysis.” The present obviousness rejection is not based on the “utility” potentially found in a reduction to practice of administering CFTR to humans, it is based upon the teaching, suggestion and motivation to do so which would reasonably produce what is claimed. Each and every method step is taught by the combination of references.
Moreover, Applicant’s argument regarding the results found in Example 3 is not persuasive. If unexpected results were found, the scope of the invention must match that of Example 3 which utilizes a particular codon optimized CFTR not claimed, in a particular lipid nanoparticle, at a particular dosage. The present claims are directed towards any CFTR. Therefore, if the claims were limited to this, DeRosa teaches the codon optimized sequence and therefore it is not novel to the present application over the prior art. Applicant must distinguish the method found in the present invention over that of DeRosa. The argument that DeRosa does not reduce to practice human administration is not persuasive as DeRosa discloses that the composition may be utilized for human administration as discussed above.
Applicant further argues that as Alton discusses “gene therapy” and not mRNA therapy, an artisan would not combine the two teachings.
Examiner disagrees. Both Alton and DeRosa are studies which utilize CTFR to treat cystic fibrosis and therefore are in the same field of invention. Moreover, Alton is to provide further evidence for a reasonable expectation of success. No steps from Alton are incorporated into the method steps of DeRosa to read on the present invention. Alton merely shows a reasonable expectation of success as established by prior art in improving FEV1 through nebulized CFTR.
Double Patenting
Claims 1-2, 14, 19, 23, 28, 31, 36, 44, 55-56, 58, 62, 68 and 71 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 7, 10-12, and 15 of U.S. Patent No. 11,173,190 (Patent ‘190) in view of Alton (2016, IDS Reference).
Although the claims at issue are not identical, they are not patentably distinct from each other because the present invention is a genus to the species of Patent ’190.
Claim 1 of the ‘190 patent recites:
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Claim 28 of the instant application recites:
A method of treating cystic fibrosis (CF) in a human subject comprising administration of a composition comprising an mRNA encoding a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein via nebulization to a human subject at a concentration of 0.5 mg/ml to 0.8 mg/ml for a duration of 135 minutes or less to achieve an increase in ppFEV1 (percent predicted forced expiratory volume in one second) from baseline by at least 3% in the human subject, and at least a 2% increase in absolute change in ppFEV1 from baseline ppFEV1 at one week following administration in the human subject. Claim 28 overlaps in scope with claim 1 of Patent ‘190 as the same concentration is utilized and method steps are the same. While Claim 1 recites a SEQ ID, it is a species to the genus claim of claim 28.
Claim 1 of the invention recites
A method of treating cystic fibrosis (CF) in a human subject comprising administration of a composition comprising an mRNA encoding a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein by nebulization at a dose between 7 mg and 25 mg that provides the human subject with at least a 3% increase in absolute change in ppFEVl (percent predicted forced expiratory volume in one second) from baseline ppFEVl at two days following the administration, wherein the dose further provides the human subject with at least a 2% increase in absolute change in ppFEVl from baseline ppFEVl at one week following the administration.
And
Claim 14 recites a method of treating cystic fibrosis (CF) in a human subject comprising nebulizing a dose between 7 mg and 25 mg of a composition comprising an mRNA encoding a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein at a dose between 7 mg and 25 mg daily, twice a week, or once a week at a regular interval for a duration of nebulization of at least 30 minutes and/or a treatment period sufficient to achieve an increase in ppFEV1 (percent predicted forced expiratory volume in one second) from baseline by at least 3% in the human subject, and at least a 2% increase in absolute change in ppFEV1 from baseline ppFEV1 at one week following administration in the human subject.
While these two independent claims do not recite the specific concentration, they overlap in scope in the same application as claim 28. Therefore, 7 mg to 25 mg would have been overlapping with claim 1 of Patent ‘190 absent to any evidence to the contrary.
Although the reference claims do not explicitly teach that the treatment results in at least a 3% increase in absolute change in ppFEV1 at two days following the administration or at least a 2% increase in absolute change in ppFEV1 from baseline ppFEV1 at one week following administration in the human subject, as each and every method step and limitation of the treatment is taught by Patent ‘190, results such as a 3% increase in absolute change in ppFEV1 at two days following the administration or at least a 2% increase in absolute change in ppFEV1 from baseline ppFEV1 at one week following administration in the human subject are inherently present as a result of the administration of the mRNA encoding CFTR to a subject.
Therefore, the present invention is rejected under non-statutory double patenting.
***
Claims 28, 31, 36, 44, 55, 56, 62, 68 and 71 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 3, 7-9, 11, and 14-16 of U.S. Patent No. 12,195,505 (Patent ‘505) in view of Karve (US20180153822; Applicant’s own work)
Although the claims at issue are not identical, they are not patentably distinct from each other because the present invention is a genus to the species of Patent ’505.
Regarding claim 28, Patent ‘505 recites a method of treating cystic fibrosis (CF) in a human subject comprising administering a composition comprising an mRNA encoding a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein at a concentration of 0.6 mg/ml to the human subject, wherein the step of administering comprises the following: (i) the composition is aerosolized using a nebulizer wherein median droplet size in the aerosolized composition is between 4 and 6 μm, and (ii) a nominal dose of the mRNA is administered to the human subject via the nebulizer over a period of time at least 30 minutes at a nebulization rate of 0.2 mL/minute to 0.5 mL/minute, wherein the composition comprises trehalose, and wherein the mRNA encoding the CFTR protein comprises SEQ ID NO: 1. (Claim 1).
However, the instant application does not require trehalose.
Karve teaches including trehalose in a composition of LNPs encapsulating mRNA (Claim 1 and 38, para. 0027, 0180-0181). Compositions comprising a 10% trehalose solution can be stably frozen (para. 0180).
It would have been obvious to one of ordinary skill in the art to include trehalose in the instant application’s composition of LNPs as taught by Karve with a reasonable expectation of success. An artisan would be motivated to include trehalose as it is known in the art according to Karve that it provides for the LNPs encapsulating mRNA to be readily frozen.
Although the claims do not explicitly teach that the treatment results in at least a 3% increase in absolute change in ppFEV1 at two days following the administration, as each and every method step and limitation of the treatment is taught by Patent ‘505, results such as a 3% increase in absolute change in ppFEV1 at two days following the administration are inherently present as a result of the administration of the mRNA encoding CFTR to a subject.
In response to Applicants’ arguments or amendments regarding the above double patenting rejections in view of Patent ‘505 and Patent ‘190,
Applicant’s arguments and amendments have been considered however they are not persuasive.
Applicant reiterates previously arguments such as instant claims recite a specific SEQ ID NO which is not recited in the Patents and therefore, there is no double patenting.
Examiner disagrees and reiterates that Applicant’s Patents provide a species SEQ ID NO for the recited genus of a CFTR mRNA of the present invention. The scope of the invention in the Patents is encompassed in the instant claims.
Applicant points to the above discussed arguments in combining Alton and DeRosa which have been refuted in the 103 rejection response above.
Applicant submits that “differences in the CFTR mRNA compositions may affect treatment results” and that other components are recited in the Patents such as “trehalose.”
If this is the case, the composition should be specifically claimed in the independent claims in order to achieve the results claimed. However, the results applicant is claiming from Example 3 are obtained through the same composition as evidenced by the instant specification detailed in Example 1 of forming the LNP composition which comprises trehalose.
New Rejections in response to Applicants’ arguments or amendments
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 36 and 68 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 36 recites “(b) the human subject has a class II mutation, optionally wherein the human subject has an F508del mutation, optionally wherein the F508del mutation is heterozygous or homozygous; or (c) the human subject has a class I mutation and a class II mutation, optionally wherein the human subject has an F508del mutation, optionally wherein the F508del mutation is heterozygous or homozygous.” This claim is indefinite because it is unclear if the “optionally” recited item is intended to be recited in the alternative (as both options recite mutations) or as an addition to the non-optional item. For the purposes of examination, the claim is interpreted as including either class I mutation, or more specifically F508del mutation or a class II mutation.
Claim 68 is indefinite in the reciting “the lipid nanoparticles” in line 2. There is no antecedent basis for the lipid nanoparticles in the claim or the claims from which it depends
Additional comments
At page 14 of the remarks, Applicants state “differences in the CFTR mRNA compositions may affect treatment results.” To advance prosecution, the examiner recommends amending the claims formulations used in the clinical studies described in Examples 2-4 comprising specific optimized CFTR mRNA, e.g., SEQ ID NOS: 28, 29 and 30 encapsulated within a lipid nanoparticle (LNP) and formulated with trehalose.
Conclusion
No claims are allowed.
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/ALEXANDRA F CONNORS/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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