DETAILED ACTION
Applicants’ arguments, filed 16 June 2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 112(b) – Indefiniteness
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 1-2, 4, 8, 10-13, and 28-31 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 31, first line, recite a dry powder microsphere composition. However, claim 1, 4th to last line and 3rd to last line recite that the composition is administered via inhalation, intranasal, or topical administration. This appears to be a method step. A single claim which claims both an apparatus and the method steps of using the apparatus is indefinite under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. See MPEP 2173.05(p)(II). In this case, claims 1 and 31 appear to recite both a composition and a method step.
For the purposes of examination under prior art, the examiner will proceed in examination with the understanding that claims 1 and 31 are drawn to composition and recite that the composition is capable of being administered in the recited manner.
Claim Rejections - 35 USC § 103 – Obviousness
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.
Claim(s) 1-2, 4, 8, 10-14, and 28-32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Smyth et al. (WO 2021/216541 A1) in view of Rizvi et al. (WO 2022/047047 A1).
Smyth et al. (hereafter referred to as Smyth) is drawn to a dry powder composition comprising polynucleotide molecules complexed with nanoparticles, as of Smyth, title and abstract. Smyth teaches a mass median aerodynamic diameter between about 3.5-4.5 micron, as of Smyth, page 4, paragraph 0009, relevant text reproduced below.
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Smyth teaches various types of polynucleotides including siRNA, mRNA, and DNA, as of page 2, paragraph 0004. Smyth teaches a dry powder inhaler as of at least page 6, paragraph 0012. Smyth teaches a mRNA COVID-19 vaccine, as of at least page 95, paragraph 00306; this is understood to read on the required nucleic acid for vaccination. Smyth also teaches the following, as of page 80, paragraph 00268, relevant text reproduced in part below.
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Smyth also teaches that the nucleic acid may encode a therapeutic protein that codes for an enzyme that is non-functional in a particular disease state, such as CFTR in cystic fibrosis, as of Smyth, page 19, paragraph 0091, reproduced below.
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Smyth does not teach 2-mercaptoethane sulfonate.
Rizvi et al. (hereafter referred to as Rizvi) is drawn to inhalable particles comprising a mucolytic agent to aid delivery, as of Rizvi, title and abstract. Rizvi teaches that the mucolytic is 2-mercaptoethane sulfonate as a sodium salt, as of Rizvi, at least page 5 lines 15-20. The “mercapto” group of this compound would have read on the required reduced free thiol because a mercaptan is a thiol. Rizvi teaches a dry powder sized around 0.1 microns to 5 microns, as of Rizvi, page 42, lines 28-34. The composition of Rizvi may be administered with liposomes, as of Rizvi, page 54, claim 42. The composition of Rizvi may include a therapeutic agent, at least as of Rizvi, page 54, claims 33-41, which list various therapeutic agents, and teaches drugs generically as of at least page 30 lines 28-30. The method of Rizvi teaches dissolution of mucus, as of Rizvi, page 4 lines 26-32.
Rizvi does not teach that the therapeutic agent is a nucleic acid.
It would have been prima facie obvious for one of ordinary skill in the art to have delivered the nucleic acid of Smyth using the 2-mercaptoethane sulfonate containing drug delivery system of Rizvi for delivery via inhalation. Rizvi is drawn to a particle comprising 2-mercaptoethane sulfonate for delivery of an active agent via dry powder inhalation, whereby the 2-mercaptoethane sulfonate aids in delivery by acting as a mucolytic and dissolving mucus. Smyth teaches that the nucleic acid must penetrate mucus to have access to live cells. As such, the skilled artisan would have been motivated to have administered the nucleic acid of Smyth via inhalation while using the 2-mercaptoethane sulfonate of Rizvi in order to have predictably degraded and/or dissolved mucus such that the nucleic acid of Smyth could have predictably had access to a live cell with a reasonable expectation of success. This would have been necessary because access to a live cell would have been necessary for mRNA, such as that taught by Smyth, to have been therapeutically effective because mRNA necessitates a live cell to translate the protein which it encodes.
As to claim 1(a), the claim requires a first population of dry-powder microsphere particles comprising sodium 2-mercaptoethane sulfonate, phospholipid, and calcium chloride, and sized in a range of 1-5 μm. Rizvi teaches all of these compounds and excipients on page 58, relevant text reproduced below with annotation by the examiner.
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Rizvi teaches the required particle size on page 56, claims 64-65.
As to claim 1(b), Smyth teaches the required lipid nanoparticles comprising nucleic acid. These particles would have been expected to have remained separate from those of Rizvi even if physically mixed together.
As to claim 1(b), the claim recites that the composition is administered by inhalation. Both Smyth and Rizvi teach this; see the abstract of Rizvi and Smyth, page 6, paragraph 0012.
As to claim 1(b), the claim recites that the transfection agent increases intracellular transfection of the nucleic acid into respiratory system cells. The teachings of Rizvi appear to indicate that the sodium 2-mercaptoethane sulfonate mucolytic would have aided in causing an active agent (which in the case of Rizvi is not a nucleic acid) to reach its target in the respiratory system. See e.g. Rizvi, page 3, relevant text reproduced below.
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As to claim 2, the skilled artisan would have expected that placement of the particles of Smyth and/or Rizvi in water or an aqueous solution would have resulted in the formation of a dispersion, which would have read on the required solution.
As to claim 4, the skilled artisan would have expected that placement of the particles of Smyth and Rizvi into a gel-forming composition would have resulted in a gel. The skilled artisan would have expected that this gel would have been capable of being administered topically.
As to claim 8, Rizvi teaches ascorbic acid and Vitamin E as of page 58, paragraph 0083.
As to claim 10, Smyth teaches various polynucleotides including siRNA, shRNA, and mRNA as of Smyth, page 2, paragraph 0004.
As to claim 11, Smyth teaches plasmid DNA as of page 2, paragraph 0004.
As to claim 12, Smyth teaches the following lipid nanoparticles, as of page 53, relevant text reproduced below.
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As to claim 13, Smyth teaches spray dried nanoparticles, as of at least Smyth, page 74, paragraph 00256.
As to claim 14, Rizvi teaches a method of administering the mucolytic agent (e.g. sodium 2-mercaptoethane sulfonate) separately as compared with the second population of particles, as of Rizvi, abstract. That the sodium 2-mercaptoethane sulfonate breaks the mucus barrier is taught as of Rizvi, page 36, relevant text reproduced below.
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As such, the skilled artisan would have expected that administration of 2-mercaptoethane sulfonate would have operated by breaking the mucus barrier; this would have read on the requirement that the method transiently disrupts the biophysical mucus barrier and opens the gate so that the therapeutic agent can be delivered.
As to claim 28, Smyth teaches a cancer vaccine on page 19, paragraph 0092.
As to claim 29, Smyth teaches a dry powder inhaler on page 6, paragraph 0012.
As to claim 30, the examiner takes the position that the phrase “increases intracellular transfection” can refer to either
of the nucleic acid containing lipid particles which come into contact with respiratory system cells, increasing the proportion of these which successfully transfect a nucleic acid; and
increasing the proportion of nucleic acid containing lipid particles which come into contact with respiratory system cells, thereby increasing the total number of transfections.
As best understood by the examiner, the skilled artisan would have expected that combining the mucolytic of Rizvi with the nucleic acid containing particles of Smyth for reason (b) but not for reason (a). In view of this expectation, there would have been a reasonable expectation that the required increase in transfection efficiency would have been either a latent property of combining Smyth and Rizvi, or that there would have been a reasonable expectation that the combination of Smyth and Rizvi would have been capable of being optimized to have achieved the required increased level of transfection.
As to claim 31, this claim appears to recite essentially the same ingredients as claim 1, but is broader in that it recites a variety of transfection efficiency enhancing agents instead of only sodium 2-mercaptoethane sulfonate. Nevertheless, as claim 31 recites sodium 2-mercaptoethane sulfonate, this claim is rejected for essentially the same reason that claim 1 is rejected.
As to claim 32, this claim appears to recite essentially the same method steps as claim 14, but is broader in that it recites a variety of transfection efficiency enhancing agents instead of only sodium 2-mercaptoethane sulfonate. Nevertheless, as claim 31 recites sodium 2-mercaptoethane sulfonate, this claim is rejected for essentially the same reason that claim 32 is rejected.
Note Regarding Reference Date: Rizvi was published on 3 March 2022. The instant application ultimately claims benefit to provisional application 63/547,629, filed on 7 November 2023. As such, Rizvi is prior art as it was published earlier than the effective filing date of the instant application. As Rizvi was published over a year earlier than the effective filing date of the instant application, none of the exceptions under AIA 35 U.S.C. 102(b)(1) or 102(b)(2) would appear to be applicable.
Claim(s) 15, 19-21, and 33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Smyth et al. (WO 2021/216541 A1) in view of Rizvi et al. (WO 2022/047047 A1), the combination further in view of VCU (https://intmed.vcu.edu/media/vcusom-t4-migration/internal-medicine/about-us/institutes-and-centers/information-sheets/VCUCF_Proper-Therapy-Order.pdf published 2021, 1 page).
Smyth is drawn to administration of nucleic acid lipid nanoparticles via inhalation. Rizvi is drawn to administering sodium 2-mercaptoethane sulfonate in combination with phospholipid and calcium chloride for mucolytic purposes along with a therapeutic agent by inhalation. See the rejection above over Smyth in view of Rizvi. Both Smyth and Rizvi teach treating cystic fibrosis; this is taught as of Smyth, claim 177 and page 19, paragraph 0091, as well as Rizvi, at least page 27 lines 15-20.
Neither Smyth nor Rizvi teach allowing a time period of 5 to 30 minutes to elapse between administering the sodium 2-mercaptoethane sulfonate and the nucleic acid.
VCU teaches that medications for cystic fibrosis should be administered in the following order.
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The hypertonic saline and Pulmozyme are mucolytics, as explained lower on the page, relevant text reproduced below.
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As such, VCU suggests administration of mucolytics prior to administration of active agents intended to act on the respiratory system such as antibiotics.
VCU does not teach a nucleic acid therapeutic.
It would have been prima facie obvious for one of ordinary skill in the art to have modified the method of Smyth in view of Rizvi to have first administered the mucolytic prior to administration of the nucleic acid lipid nanoparticle. VCU teaches that administration of a mucolytic prior to a drug to be delivered such as an antibiotic helps deliver the antibiotic to the lungs. As such, the skilled artisan would have been motivated to have administered the mucolytic of Rizvi (e.g. 2-mercaptoethane sulfonate) prior to the nucleic acid contained lipid nanoparticle of Smyth in order to have allowed for the nucleic acids of Smyth to have predictably penetrated deeper into the lungs with a reasonable expectation of success.
As to claim 15, the claim recites a time period of 5 to 30 minutes between the administration of the 2-mercaptoethane sulfonate and the nucleic acid in a lipid nanoparticle. VCU is silent as to the time period between administration of the mucolytic and the additional therapeutic agents. Nevertheless, VCU clearly teaches that the mucolytic and additional therapeutic agents intended to penetrate deep into the lung are administered in separate steps, with the mucolytic administered first. As such, the skilled artisan would have been motivated to have optimized the method of Smyth in view of Rizvi and VCU to have achieved the recited time period between administration of the mucolytic and the nucleic acid with a reasonable expectation of success. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144.05(II)(A). In this case, the general conditions of first administering a mucolytic followed by administering an active agent intended to penetrate into the lungs has been taught by VCU. As such, it would not have been inventive for the skilled artisan to have discovered the optimum or workable ranges of time periods between administering the mucolytic and administering the additional active agent (e.g. the nucleic acid) via routine experimentation.
As to claim 19, Smyth teaches various polynucleotides including siRNA, shRNA, and mRNA as of Smyth, page 2, paragraph 0004, as well as plasmid DNA in the same paragraph.
As to claim 20, Smyth teaches plasmid DNA as of page 2, paragraph 0004.
As to claim 21, Smyth teaches siRNA, shRNA, and mRNA as of Smyth, page 2, paragraph 0004.
As to claim 33, this claim appears to recite essentially the same method steps as claim 15, but is broader in that it recites a variety of transfection efficiency enhancing agents instead of only sodium 2-mercaptoethane sulfonate. Nevertheless, as claim 31 recites sodium 2-mercaptoethane sulfonate, this claim is rejected for essentially the same reason that claim 15 is rejected.
Note Regarding Reference Date of VCU Reference: The Wayback Machine® is a digital library maintained by the Internet Archive (a non-profit organization) for viewing archived versions of websites. Simply, the Wayback Machine® uses software programs, known as crawlers, to surf the internet and automatically store copies of web objects (web pages, images, videos, etc.), preserving these objects as they exist at the point and time of capture. These web objects are stored as web captures. Each capture has a time stamp including the year/month/day/hour/minute/second the capture was made and the URL of the original website. Accordingly, the Wayback Machine® provides the ability to view and browse internet information that may no longer be available on the original website.
Publications obtained via the Wayback Machine® are prima facie deemed to be publicly accessible at the date and time provided in the time stamp. The burden then shifts to the applicant should they wish to challenge the authenticity, reliability or accessibility of such information. See MPEP 2128(II)(E). In this case, the VCU reference appears to have been published on 22 October 2021, as of the time stamp provided by the Wayback Machine®. As such, VCU is understood to be prior art under AIA 35 U.S.C. 102(a)(1) as it appears to have been published prior to the effective filing date of the instant application.
Claim(s) 18 and 24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Smyth et al. (WO 2021/216541 A1) in view of Rizvi et al. (WO 2022/047047 A1), the combination further in view of VCU (https://intmed.vcu.edu/media/vcusom-t4-migration/internal-medicine/about-us/institutes-and-centers/information-sheets/VCUCF_Proper-Therapy-Order.pdf published 2021, 1 page), the combination further in view of Charrier et al. (Orphanet Journal of Rare Diseases, Vol. 9:189, 2014, pages 1-11).
Smyth is drawn to administration of a nucleic acid to the lungs. Rizvi is drawn to administration of a mucolytic prior to administration of an active agent in order to improve delivery of the active agent, as of page 36 of Rizvi. VCU is drawn to administration of the mucolytic prior to administration of other therapeutic agents. See the above rejection over Smyth in view of Rizvi by themselves. Rizvi teaches 2-mercaptoethane sulfonate as a mucolytic, as of Rizvi, at least page 5 lines 15-20.
None of the above references teach cysteamine.
Charrier et al. (hereafter referred to as Charrier) is drawn to cysteamine as a mucoactive agent, as of Charrier, page 1, title and abstract. Charrier refers to cysteamine as a mucolytic, as of Charrier, page 1, “Results” and “Conclusions” section of abstract. Charrier teaches administration via dry powder inhalation, as of Charrier, page 10, top paragraph (reproduced below) and last paragraph in “Conclusion” section.
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The examiner understands the above-reproduced text to teach that dry powder inhalation is preferred over nebulization for delivery of cysteamine via inhalation.
Charrier does not teach a nucleic acid therapeutic.
It would have been prima facie obvious for one of ordinary skill in the art to have combined the cysteamine of Charrier into the method of Smyth in view of Rizvi. Smyth and Rizvi are drawn to a method of administering an active agent to the lungs, and Rizvi teaches the inclusion of 2-mercaptoethane sulfonate as a mucolytic. Charrier teaches that cysteamine also acts as a mucolytic, and suggests administration of cysteamine via inhalation. As such, the skilled artisan would have been motivated to have combined the mucolytic of Rizvi, which is 2-mercaptoethane sulfonate, with the mucolytic of Charrier, which is cysteamine, in order to have predictably lysed mucus in the lung in order to have predictably improved delivery of an active agent with a reasonable expectation of success. Combining prior art elements (e.g. 2-mercaptoethane sulfonate and cysteamine) according to known methods to yield predictable results (action as a mucolytic) is prima facie obvious. See MPEP 2143, Exemplary Rationale A.
Response to Arguments Regarding CIL-0X
In applicant’s prior response on 8 December 2025, applicant previously argued that a formulation comprising sodium 2-mercaptoethane sulfonate results in a synergistic effect not taught by the prior art, as of pages 11 and 17 of applicant’s prior response on 8 December 2025. In support of this position, applicant has set forth the following figure on page 12 of applicant’s prior response.
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The figure reproduced above-right appears to be fairly similar (but not exactly the same) as figure 6 of the instant application, which is reproduced below.
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In response, the examiner previously argued that there is no nexus between the recited CIL-0X in the above-reproduced figure and the claimed mucolytic, which comprises 2-mercaptoethane sulfonate in claim 1. The examiner made these arguments primarily on pages 16-17 of the prior office action mailed on 16 January 2026.
Applicant has addressed the examiner’s argument regarding a lack of nexus on pages 13-14 of applicant’s most recent response on 16 June 2026 (hereafter referred to as applicant’s most recent response). These arguments have been presented in the section entitled “NEXUS BETWEEN CIL-0X AND SODIUM 2-MERCAPTOETHANE SULFONATE.” These arguments have been addressed by the examiner below.
In the above-indicated section of applicant’s response, applicant makes the following argument, as of page 13, bottom paragraph, relevant text reproduced below.
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As an initial matter, the examiner notes that the instant specification as filed appears to have only 160 numbered paragraphs. Therefore, there is no paragraph [0192] in the originally filed specification. However, the instant application was published as US 2025/0144237 A1. This publication has different paragraph numbering and does include a paragraph 0192, which is reproduced below.
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This paragraph does disclose that CIL-0X is transfection enhancing agent. However, nothing in this paragraph discloses that the transfection enhancing agent is necessarily 2-mercaptoethane sulfonate or thiol derived therefrom.
Applicant then makes the following argument, as of the top paragraph of page 14, which is reproduced below.
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As best understood by examiner, paragraph [0121] refers to the relevant paragraph from the publication of the instant application and is reproduced below.
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This paragraph does indeed disclose that the transfection efficiency enhancing agent may be sodium 2-mercaptoethane sulfonate. However, the paragraph also discloses that the transfection efficiency enhancing agent may be cysteamine. As such, this paragraph would appear to indicate that CIL-0X, being a transfection efficacy agent, may be either sodium 2-mercaptoethane sulfonate or cysteamine, and therefore fails to establish the chemical identity of CIL-0X. Additionally, instant claim 32 recites a wide variety of transfection efficiency enhancing agents other than sodium 2-mercaptoethane sulfonate or cysteamine, including but not limited to ascorbic acid, DNAse, and bromohexine. As such, nothing in applicant’s arguments on page 13, last paragraph and page 14, top paragraph establishes that CIL-0X is sodium 2-mercaptoethane sulfonate.
Applicant then makes the following argument on page 14 of applicant’s response, which is reproduced below.
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The examiner has reproduced paragraph 0194 in part below.
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This paragraph merely states that CIL-0X is the transfection enhancing composition. It does not state that the transfection enhancing composition that is CIL-0X is sodium 2-mercaptoethane sulfonate, as opposed to one of many other compounds identified as transfection enhancing agents in the instant application.
As such, nothing in applicant’s response appears to show a nexus between the compound labeled as CIL-0X and sodium 2-mercaptoethane sulfonate (sometimes abbreviation as MESNA). In view of this, the examiner maintains the position that the results in instant figure 6 are insufficient to overcome the previously applied rejection based upon unexpected results because applicant has not established that the results present in figure 6, which include the material known by the abbreviation “CIL-0X” are commensurate with the claim scope.
As such, the balance of evidence still appears to indicate a lack of nexus between CIK-0X, as of the instant specification, and the sodium 2-mercaptoethane sulfonate. As such, the data in figure 6 is still understood to be insufficient to overcome the previously applied rejection for essentially the same reason that was provided in the prior office action on page 17.
Response to Arguments Regarding Obviousness Rejection
Applicant has presented arguments regarding the previously presented obviousness rejections, as of applicant’s response on 16 June 2026 (hereafter referred to as applicant’s response). These arguments have been addressed below.
Applicant makes the following argument on the top half of page 15 of applicant’s response.
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In view of this argument, the examiner reviewed the Smyth reference for further information regarding this issue. The examiner notes Smyth, page 80, which teaches the following, as of the paragraph reproduced below.
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The teachings of the above-reproduced paragraph appear to indicate that only about 25% of siRNA containing lipid nanoparticles diffused through the simulated mucus layer within 5 hours. This would appear to indicate that there is significant room for improvement, as the skilled artisan would have desired 100% of the particles to have diffused through the simulated mucus layer. As such, the skilled artisan would have been motivated to have made modifications intended to have increased the proportion of particles diffusing across the mucus layer. The skilled artisan would have expected that a mucolytic, such as that taught by Rizvi, would have weakened the mucus layer and allowed for more particles to have passed through. As such, the above-cited paragraph appears to bolster the examiner’s case for why there would have been a motivation for the skilled artisan to have administered the mucolytic of Rizvi.
Applicant then argues that Smyth is drawn to intracellular activity whereas Rizvi is drawn to extracellular mucus modification, as of applicant’s response, bottom paragraph of page 15. The implication of this appears to be that Smyth and Rizvi should not be combined because Smyth is drawn to intracellular activity whereas Rizvi is drawn to extracellular activity.
This is not persuasive. While the particle of Smyth indeed appears to be intended for intracellular delivery, the particle must go through the extracellular environment to reach the cell for which delivery is intended. As such, prior art references drawn to extracellular delivery are relevant to the issue of intracellular delivery; and as such, Smyth and Rizvi are sufficiently similar references to be combined.
In applicant’s response on page 16, applicant argues that Smyth’s teachings regarding mucus permeability are not teachings regarding mucolysis. This is not persuasive. The examiner does not dispute that mucus permeability and mucolysis are different phenomena. Mucus permeability refers to the ability of a particle to travel through mucus, whereas mucolysis refers to the act of breaking up mucus. Nevertheless, as mucus presents a barrier to permeability, the skilled artisan would have expected that mucus that has undergone mucolysis would have presented a lower barrier to permeability. The VCU reference appears to provide support for this position, in that VCU indicates that therapeutic agents administered after administration of a mucolytic can penetrate deeper into the lungs because the mucolytic broke up lung mucus. As such, there would have been a reasonable expectation that causing mucolysis would have resulted in increased permeability of particles through mucus.
Applicant then makes the following argument as of the top of page 17 of applicant’s response.
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This is not persuasive. Rizvi appears to teach combination of the mucolytic composition used in the method of Rizvi with a wide variety of drugs. For example, the entirety of page 14 of Rizvi is drawn to drugs that can be combined with the particles used in the method of Rizvi. As this wide variety of active agents appear to be stable in the presence of the mucolytic of Rizvi, the skilled artisan would have had a reasonable expectation that the particles of Smyth would have been stable in the presence of the mucolytic of Rizvi. Obviousness requires a reasonable expectation of success (including that the combined elements of each reference be stable together), not absolute predictability. See MPEP 2143.02, especially MPEP 2143.02(II). Applicant may present evidence showing the lack of a reasonable expectation of success, as of MPEP 2143.02(II); however, applicant’s assertion that the lipid nanoparticles of Smyth would not be stable in the presence of the mucolytic compounds of Rizvi is not evidence of a lack of a reasonable expectation of success.
Applicant then makes the following argument as of the bottom of page 17, reproduced below.
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Applicant then argues that the mucolytic activity of mercaptoethane sulfonic acid (abbreviated as MESNA) does not address the intracellular barriers to transfection. This is not persuasive because intracellular barriers to transfection are not the only barriers to transfection that exist. There are also extracellular barriers to transfection; namely, issues pertaining to the lipid nanoparticle being able to reach the cells intended to be transfected. The mucus barrier is a relevant physical barrier that prevents the lipid nanoparticles of Smyth from reaching the cells intended to be transfected when administering via inhalation. The skilled artisan would have expected the mucolytic of Rizvi to have been able to have broken down this physical barrier and thereby to have predictably improved transfection efficacy with a reasonable expectation of success.
In a similar vein, applicant argues the following on page 18, middle paragraph, relevant text reproduced below.
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It is the examiner’s position that, even if, purely en arguendo, Rizvi’s mucolytic system only improves particle access but does not increase transfection using any other biochemical mechanism, this would be sufficient to serve as a motivation to combine Smith with Rizvi. The skilled artisan would have understood that if the proportion of particles that can access the cells that are in need of transfection were to have been increased, then the total number of transfections that would have occurred successfully would have been increased. This would have been the case even if the proportion of particles in the presence of a cell to be transfected that successfully transfected the cell were to have remained constant.
Applicant then makes the following arguments on page 19, relevant text reproduced below.
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Even if, purely en arguendo, this is true, it is not persuasive. Rizvi teaches administration of 2-mercaptoethane sulfonate via inhalation. Therefore, the skilled artisan would have expected that, even if, purely en arguendo, applicant had discovered that administration of 2-mercaptoethane sulfonate via inhalation operates by a different molecular mechanism as compared with that which described by Rizvi, it would appear that this amounts to applicant having discovered a scientific basis for the functioning of Rizvi. The discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer. See MPEP 2112(I). This feature need not have been recognized at the time of filing. See MPEP 2112(II).
Applicant then presents additional arguments regarding instant figure 6, including the following argument.
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This argument does not appear to be commensurate in scope with the claimed requirements. This is because this argument would appear to be commensurate in scope only with hypothetical method claims drawn to administration to patients with normal airway mucus. This argument is not be commensurate in scope with composition claims and claims drawn to the method of making the composition. This is because such claims are drawn to the composition itself, not to the method for its use or to a method in which the patient population to whom the composition is administered has been limited. See MPEP 2112, 2114(II), and 2144(IV).
Applicant then makes the following argument, as of the bottom of page 20, relevant text reproduced below.
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These arguments continue on through the entirety of page 21 of applicant’s response.
This is not persuasive because it appears to drawn to the data in figure 6. This figure fails to present an adequate comparison between the claimed invention and prior art. This is at least because the reference to pretreatment with CIL-0X appears to refer to a tested group in figure 6. However, the chemical identity of “CIL-0X” has not been adequately presented in the file record. As such, data associated with figure 6 is not understood to be probative of non-obviousness. See the section above entitled “Response to Arguments Regarding CIL-0X.”
Applicant makes arguments related to alleged unexpected results, as of applicant’s response, page 22. These arguments are not persuasive because they rely upon figure 6 of the instant application. There is no nexus between the data in figure 6 and the instantly claimed invention for the reasons explained above.
Applicant then presented arguments requirement (b) in new claim 33 and in claim 15, which has been amended to include this limitation, as of page 22, last two lines and page 23 of applicant’s response. These arguments appear to be moot in view of the newly cited reference VCU (https://intmed.vcu.edu/media/vcusom-t4-migration/internal-medicine/about-us/institutes-and-centers/information-sheets/VCUCF_Proper-Therapy-Order.pdf published 2021, 1 page). As such, these arguments have not been addressed substantively by the examiner.
Applicant then presented arguments regarding claims 18 and 24, as of page 24 of applicant’s response. The following arguments have been reproduced below.
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The skilled artisan would have been motivated to have combined the mucolytic of Rizvi with the nucleic acid of Smyth. This is explained in the rejection above, as well as in the prior office action mailed on 16 January 2026 on pages 8-9.
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 ISAAC SHOMER whose telephone number is (571)270-7671. The examiner can normally be reached 7:30 AM to 5:00 PM Monday Through Friday.
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ISAAC . SHOMER
Primary Examiner
Art Unit 1612
/ISAAC SHOMER/ Primary Examiner, Art Unit 1612
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