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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim Numbering – Objection
The instant claims are objected to for the following reasons:
The numbering of the claims in the claim set on 6 November 2023 appears to be improper. In the claim set on 6 November, the claims are numbered A1-A19 and B1-B13. In contrast, claims should be numbered with numbers as opposed to combinations of letters and numbers.
Appropriate correction is required.
For the purposes of examination under prior art, claims A1-A19 are understood to be claims 1-19, and claims B1-B13 are understood to be claims 20-32. This issue should be corrected in the next office action.
Election/Restrictions
Applicant’s election without traverse of Group II, claims 20-32 in the reply filed on 6 November 2025 is acknowledged.
Claims 1-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6 November 2025.
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.
Claim(s) 20, 25-27, and 29-31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schariter et al. (US 2020/0306191 A1) in view of Tenchov et al. (ACS Nano, Vol. 15, 2021, pages 16982-17015 and supplemental pages 1-10).
Schariter et al. (hereafter referred to as Schariter) is drawn to lipid nanoparticles, abbreviated as “LNP.” The lipid nanoparticles of Schariter comprise mRNA, as of at least Schariter, paragraphs 0052-0054. The lipid nanoparticles of Schariter are for delivery to a mammalian cell, as of Schariter, paragraphs 0357-0358.
Schariter does not teach forming liposomes separate from the lipid nanoparticles, and combining said liposomes with the lipid nanoparticles.
Tenchov et al. (hereafter referred to as Tenchov) is drawn to lipid nanoparticles and liposomes for mRNA vaccine delivery, as of Tenchov, page 16982, title and abstract. Tenchov teaches the following on page 16984, left column, first paragraph below figure 4, relevant text reproduced below with annotation by the examiner.
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Tenchov is not anticipatory because Tenchov does not appear to teach an embodiment wherein a lipid nanoparticle is combined with a giant unilamellar vesicle.
It would have been prima facie obvious for one of ordinary skill in the art to have combined the lipid nanoparticle of Schariter with the giant unilamellar vesicle of Tenchov. Schariter is drawn to lipid nanoparticles, and Schariter teaches that the lipid nanoparticles of Schariter are intended for delivery to a mammalian cell, as of Schariter, paragraphs 0357-0358. The giant unilamellar vesicle of Tenchov appears to act as a model for a cell, and the lipid nanoparticle of Schariter is intended for delivery to a cell. As such, the skilled artisan would have been motivated to have combined the lipid nanoparticle of Schariter with the giant unilamellar vesicle of Tenchov in order to have predictably tested the ability of the mRNA lipid nanoparticle of Schariter to have predictably delivered active agent to a cell with a reasonable expectation of success.
As to claim 20, Tenchov teaches giant unilamellar vesicles. As such, the skilled artisan would have been motivated to have formed giant unilamellar vesicles.
As to claim 20, Schariter teaches preparing lipid nanoparticles comprising an mRNA molecule.
As to claim 20, the claim requires generating a liposome-lipid nanoparticle formulation by incorporating the liposomes in the lipid nanoparticles. The skilled artisan would have been motivated to have combined the lipid nanoparticles of Schariter with the giant unilamellar vesicle of Tenchov in order to have predictably modeled the interactions of the lipid nanoparticle of Schariter with cells, as the giant unilamellar vesicle of Tenchov appears to be a model for a cell. The skilled artisan would have expected this method to have generated a liposome-lipid nanoparticle formulation.
As to claim 25, Schariter teaches mixing lipid components in organic solvent with mRNA in acidic buffer, as of paragraph 0165 of Schariter. Schariter teaches an ionizable lipid as a lipid component as of at least paragraphs 0114-0115 of Schariter. Schariter also teaches dialysis to remove ethanol in paragraph 0110.
As to claim 26, the skilled artisan would have expected that the mRNA molecule would have retained its integrity upon combination with the liposome as there do not appear to be organic solvents or surfactants present that would have destroyed the integrity of the mRNA.
As to claim 27, the skilled artisan would have expected that combination of the lipid nanoparticle comprising mRNA of Schariter and the giant unilamellar vesicle would have resulted in fusion rather than aggregation.
As to claim 29, Schariter teaches determining particle size in paragraph 0535, polydispersity index in paragraph 0534, and zeta potential in paragraph 0534. Although this teaching is for the lipid nanoparticle prior to combination with the giant unilamellar vesicle, the skilled artisan would have been motivated to have conducted this step on the combination of the lipid nanoparticle with the giant unilamellar vesicle.
As to claim 30, Schariter teaches filtering as of at least paragraph 0109.
As to claim 31, Schariter teaches mRNA encoding an antigen of a pathogen, as of at least paragraphs 0359-0360 of Schariter.
The examiner has decided not to reject claim 32 on this ground of rejection. Regarding claim 32, the examiner takes the position that the lipid nanoparticle of Schariter, in the absence of combining with the liposome, would have been suitable for treating or preventing one of the recited conditions; see the above rejection of claim 31. However, the examiner takes the position that the skilled artisan would have expected that the step of combining the lipid nanoparticle of Schariter with a giant unilamellar vesicle would have destroyed the ability of the lipid nanoparticle of Schariter to have been effective. As such, the examiner has decided not to reject claim 32 over this combination of references due to lack of a reasonable expectation of success. This issue is expounded upon in greater detail below in the rejection for lack of enablement.
The examiner has also decided not to reject claim 24. Even if, purely en arguendo, the skilled artisan would have been motivated to have used sonication to have prepared the lipid nanoparticle comprising mRNA, this would not have been sufficient to render the instant claims obvious. This is because claim 24 recites sonication of the liposome, not the lipid nanoparticle. The examiner cited Tenchov to teach a giant unilamellar liposome. The skilled artisan would have understood that sonication is used in the art to reduce liposome sizes. As such, the skilled artisan would not have been motivated to have sonicated a giant liposome because of the expectation that by doing so, the giant liposome would have been broken into smaller liposomes and would no longer have been giant.
The examiner has decided not to reject claim 22 on this ground of rejection because the skilled artisan would have expected that the combination of the lipid nanoparticle of Schariter with the giant unilamellar vesicle of Tenchov would have been expected to have disrupted the supramolecular assembly of the mRNA/LNP structure. This issue is discussed in further detail in the rejection for lack of enablement set forth below.
Claim(s) 20-21, 23, and 25-31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schariter et al. (US 2020/0306191 A1) in view of Tenchov et al. (ACS Nano, Vol. 15, 2021, pages 16982-17015 and supplemental pages 1-10), the combination further in view of Domingues et al. (Langmuir, Vol. 26(13), 2010, pages 11077-11084).
Schariter is drawn to a lipid nanoparticle intended to deliver mRNA to a cell. Tenchov is drawn to the use of a giant unilamellar liposome as a model for a cell. See the rejection above over Schariter in view of Tenchov.
Neither Schariter nor Tenchov teach that the liposome comprises POPG.
Domingues et al. (hereafter referred to as Domingues) is drawn to a giant unilamellar liposome which may comprise palmitoyloleoyl phosphatidylglycerol (POPG) as a model of a bacterial or mammalian cell membrane, as of Domingues, title and abstract.
It would have been prima facie obvious for one of ordinary skill in the art to have made the giant unilamellar vesicles of Tenchov using POPG, as taught by Domingues. Tenchov is drawn to using giant unilamellar vesicles as models of cell membranes, but is silent as to the use of POPG in said models. However, Domingues teaches the incorporation of POPG in giant unilamellar vesicles intended as models for cell membranes. As such, the skilled artisan would have been motivated to have combined the POPG of Domingues with the giant unilamellar vesicle of Tenchov for predictable formation of a giant unilamellar vesicle intended as a model for a cell membrane with a reasonable expectation of success.
As to claim 20, Tenchov teaches giant unilamellar vesicles. As such, the skilled artisan would have been motivated to have formed giant unilamellar vesicles.
As to claim 20, Schariter teaches preparing lipid nanoparticles comprising an mRNA molecule.
As to claim 20, the claim requires generating a liposome-lipid nanoparticle formulation by incorporating the liposomes in the lipid nanoparticles. The skilled artisan would have been motivated to have combined the lipid nanoparticles of Schariter with the giant unilamellar vesicle of Tenchov in order to have predictably modeled the interactions of the lipid nanoparticle of Schariter with cells, as the giant unilamellar vesicle of Tenchov appears to be a model for a cell. The skilled artisan would have expected this method to have generated a liposome-lipid nanoparticle formulation.
As to claim 21, Domingues teaches POPG as of page 11077, abstract.
As to claim 23, Domingues teaches the following procedure for producing the giant unilamellar vesicle, as of page 11078, right column, relevant text reproduced below.
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This method includes steps of introducing the lipids in chloroform, evaporating the chloroform, then hydrating with a sugar containing aqueous solution. This sugar containing solution is understood to read on the required buffer solution because sugar is an osmotic buffer.
As to claim 25, Schariter teaches mixing lipid components in organic solvent with mRNA in acidic buffer, as of paragraph 0165 of Schariter. Schariter teaches an ionizable lipid as a lipid component as of at least paragraphs 0114-0115 of Schariter. Schariter also teaches dialysis to remove ethanol in paragraph 0110.
As to claim 26, the skilled artisan would have expected that the mRNA molecule would have retained its integrity upon combination with the liposome as there do not appear to be organic solvents or surfactants present that would have destroyed the integrity of the mRNA.
As to claim 27, the skilled artisan would have expected that combination of the lipid nanoparticle comprising mRNA of Schariter and the giant unilamellar vesicle would have resulted in fusion rather than aggregation.
As to claim 28, Domingues teaches POPC and POPG as of page 11078, right column, though it is unclear if the relative amounts of these ingredients are discussed. Nevertheless, the skilled artisan would have been motivated to have optimized the relative amounts of these ingredients. 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 a liposome comprising POPG and other lipids have been taught by Domingues. As such, it would not have been inventive for the skilled artisan to have determined the optimum or workable ranges of ratios between POPG and other lipids via routine experimentation.
Also as to claim 28, the examiner notes that the claim recites that the final concentration of POPG is optimized based on the inflammatory response in an in vitro or in vivo model. The examiner acknowledges that inflammation does not appear to be discussed in Domingues. Nevertheless, the reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See MPEP 2144(IV). In this case, it is the examiner’s position that even if, purely en arguendo, the reason that the skilled artisan would have optimized the concentration of POPG in the prior art is different from the recited reason of affecting the inflammatory response; nevertheless, there is still a prima facie case of obviousness for the reasons set forth above.
As to claim 29, Schariter teaches determining particle size in paragraph 0535, polydispersity index in paragraph 0534, and zeta potential in paragraph 0534. Although this teaching is for the lipid nanoparticle prior to combination with the giant unilamellar vesicle, the skilled artisan would have been motivated to have conducted this step on the combination of the lipid nanoparticle with the giant unilamellar vesicle.
As to claim 30, Schariter teaches filtering as of at least paragraph 0109.
As to claim 31, Schariter teaches mRNA encoding an antigen of a pathogen, as of at least paragraphs 0359-0360 of Schariter.
Claim Rejections - 35 USC § 112(a) – Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 22 and 32 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for conducting the steps of forming liposomes, preparing mRNA-LNPs, and mixing these together, does not reasonably provide enablement for a method wherein the thus-formed composition can successfully treat or prevent a disease. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. See MPEP 2164.01(a). The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by MPEP 2164.01(a) and are set forth below.
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved; see MPEP 2164.03. Keeping that in mind, the factors set forth in MPEP 2164.01 are relevant to the instant fact situation for the following reasons:
1. The nature of the invention, state and predictability of the art, and relative skill level (B)-(E)
The invention relates to a method of formulating a composition comprising mRNA and using said composition. The relative skill of those in the art is high, that of an MD or PhD. That factor is outweighed, however, by the unpredictable nature of the art. As illustrative of the state of the art, the examiner cites the following references.
First, the examiner provides a brief overview of liposomes and lipid nanoparticles.
Regarding liposomes, the skilled artisan would have understood that a liposome is a particle comprising a lipid bilayer delimiting an interior aqueous phase. See e.g. Robson et al. (Frontiers in Pharmacology, Vol. 9, Article 80, February 2018, pages 1-8). Specifically, the figure on page 3 of Robson is particularly relevant and is reproduced below.
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As such, a liposome comprises a lipid bilayer delimiting an interior aqueous phase, which may include cargo. For the purposes of examination under prior art, a cell is not considered to be a liposome because the term “liposome” is understood to refer to synthetic structures and not to cells.
The claims rejected herein also recite preparing a LNP formulation comprising an mRNA molecule. The abbreviation “LNP” refers to “lipid nanoparticle.” As of the earliest effective filing date of the instant application of 5 November 2022, lipid nanoparticles comprising mRNA were well-known for delivering mRNA, having been used in COVID-19 vaccines from Moderna and Pfizer/BioNTech prior to the effective filing date of the instant application. To provide general information regarding mRNA-bearing lipid nanoparticles, the examiner cites Schoenmaker et al. (International Journal of Pharmaceutics, Vol 601, 2021,120586, pages 1-13). Schoenmaker et al. (hereafter referred to as Schoenmaker) is drawn to the mRNA lipid nanoparticle COVID-19 vaccines, as of Schoenmaker, page 1, title and abstract. Schoenmaker teaches the following representations of the interior structure of a mRNA lipid nanoparticle comprising nucleic acid, as of Schoenmaker, page 5, figure 3, reproduced below.
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The text of Schoenmaker reviewing figure 3, as of the paragraph bridging pages 4-5 of Schoenmaker indicates a degree of unpredictability with respect to the structure of a mRNA lipid nanoparticle. Regardless, the interior of the mRNA lipid nanoparticles used in the COVID-19 vaccines appears to be drawn to a structure that is somewhere between the extremes of an aqueous core structure such as a liposome and a lipidic core structure. It is also unpredictable as to whether the surface of the particle comprises ionizable cationic lipid (i.e. DLin-MC3-DMA), anionic mRNA, or both.
As best understood by the examiner, despite the significant amount of work done in the field of lipid nanoparticle mRNA delivery for vaccine development during the COVID-19 pandemic, there still appears to be a high level of unpredictability related to how lipid nanoparticle mRNA delivery vehicles operate. This is evident given the fact that Schoenmaker suggests possible structures for lipid nanoparticles but appears unsure about which structural model accurately represents the lipid nanoparticle. The examiner also cites Eygeris et al. (Accounts of Chemical Research, Vol. 55, 2022, pages 2-12), which is drawn to lipid nanoparticles for mRNA and siRNA delivery, as of the title and abstract of the reference. However, Eygeris teaches a number of unanswered questions with respect to lipid nanoparticles on page 9, figure 5, relevant figure reproduced below.
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With all of this being said, what does appear to be known is that cationic lipids, whether ionizable or permanently cationic, are needed for successful operation of the RNA containing lipid nanoparticle. See e.g. Eygeris, page 4, left column, relevant text reproduced below.
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In this case, the ionizable lipids described above would appear to be ionizable cationic lipids rather than ionizable anionic lipids because only ionizable cationic lipids would have been able to have become positively charged inside the acidic endosomes; in contrast, ionizable anionic lipids would have been neutral in an acidic environment.
What would have also been expected would have been that the introduction of anionic lipids to a cationic lipid containing particle would have resulted in significant structural changes that would likely have compromised the effectiveness of the particle at delivering nucleic acids. In support of this position, the examiner cites Hafez et al. (Gene Therapy, Vol. 8, 2001, pages 1188-1196). Hafez et al. (hereafter referred to as Hafez) is drawn to the mechanism by which cationic lipids facilitate the intracellular delivery of nucleic acids, as of Hafez, page 1188, title and abstract. Hafez teaches the following on page 1191, right column, relevant paragraph reproduced below.
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The examiner notes the following. First, the abbreviation “DOPS” refers to dioleoyl phosphatidylserine, which is a well-known ionizable anionic lipid with a net negative formal charge at neutral and basic pH. The abbreviation “LUV” refers to a large unilamellar vesicle, which is a liposome but would appear to be too large to be a lipid nanoparticle – Hafez is not anticipatory for at least that reason. DOTAP and DODAC are cationic lipids and DOPE is a zwitterionic lipid.
As such, the above-reproduced text clearly teaches that combination of an anionic lipid in a vesicular form with a cationic lipid assembly will result in a change to the supramolecular assembly that is so significant that its effects can be seen with the naked eye. This would appear to indicate that it would have been highly unpredictable for liposomes to be able to be combined with mRNA lipid nanoparticles (that would have contained cationic lipids) in the absence of disrupting the supramolecular assembly of the structure, as required by claim 22. Additionally, the skilled artisan would have expected that the milky structure of larger particles would have inhibited the ability of the composition to successfully administer mRNA such that the mRNA becomes transfected and is capable of treating or preventing diseases, as required by claim 32. This determination is made in at least in view of Schoenmaker, which teaches the necessity of using particles sized 60-100 nm and to have prevented aggregation during storage in order to have achieved successful delivery of the nucleic acid and thereby to have achieved therapeutic effects, as of Schoenmaker, page 4, left column, section 2.2. The requirement that particles must be in a particular size range is also taught as of Eygeris, page 7, left column, bottom paragraph.
As such, there would have reasonable expectation that had the method steps of claim 22 been performed, that the ability of the method steps to have not disrupted the supramolecular assembly of the lipid nanoparticle, as required by claim 22, would have been highly unpredictable. Also, it would have been highly unpredictable that the product formed from conducting the method steps of claims 20 and 22 would have retained the ability to deliver mRNA in a manner that the mRNA could have produced protein in vivo and have treated or prevented the disorders recited by claim 32.
The breadth of the claims (A)
The instant claims being rejected here are broad because the claims fail to limit:
The lipids that make up the liposome is not limited by claims 22 and 32;
The lipids that make up the lipid nanoparticle are not limited by the recited claims;
The use of a permanently cationic lipid as compared with an ionizable cationic lipid is not limited by the recited claims; the teachings of Eygeris would appear to indicate significant differences between these as of the paragraph bridging page 3, left column and right column;
The presence, absence, or chemical nature of helper lipids and structural lipids, which are discussed in Schoenmaker, are not recited by the claims;
The presence or absence of PEGylated lipids, which are discussed in both Schoenmaker and Eygeris, are not recited by the claims;
The manner in which the liposome and lipid nanoparticle are combined is not recited by the claims; for example, the claims do not recite the temperature or pH at which this combination occurs;
While claim 29 (which is not rejected as lacking enablement) recites measuring particle size, polydispersity index, and zeta potential, the particle sizes and zeta potentials of the product formed by combining the liposome and lipid nanoparticle are not recited by the claims.
3. The amount of direction or guidance provided and the presence or absence of working examples (F)-(G)
The specification provides a number of working examples. Working example 1 is drawn to the preparing of DOPG liposomes, which is reproduced below from page 7 of the instant specification.
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The above-reproduced text appears to indicate the presence of a product made only from an ionizable cationic lipid and mRNA. The chemical identity of the ionizable cationic lipid is not recorded. (The examiner notes here that the only cationic lipid specifically named in the specification is DOTAP, which is named on page 9, paragraph 0033, and DOTAP is a permanently cationic lipid rather than an ionizable lipid, e.g. as required by claim 25). There is no evidence of the presence of a helper lipid, structural lipid, or PEGylated lipid, all of which appear to be necessary components of the lipid nanoparticles discussed by Schoenmaker that are used in the commercially available COVID-19 vaccines. While the specification discusses electron microscopy in the above-reproduced paragraph, the results of such electron microscopy experiments such as the particle size do not appear to be disclosed in the specification. As such, there does not appear to be a nexus between the formulation described above and the required LNP formulation of the instant claims.
The instant specification later discusses a broad range of mRNA to POPG ratio of 1000:1 to 1:1000 on a wt/wt or mol/mol basis, as of page 8, paragraphs 0025-0027 of the instant specification. While the specification discloses that the mRNA/LNP structure is undisrupted on page 8, end of paragraph 0025, the specification does not disclose what ratios would have resulted in an undisrupted structure and what rations would have resulted in a disrupted structure. Also, the specification does not disclose what the physical chemistry of an undisrupted structure actually is. This is relevant because a liposome and a lipid nanoparticle would have had particular structures, and had the liposome and lipid nanoparticle structures been incorporated together or had hydrogen bonds been formed between the cationic lipid of the LNP and the anionic lipid of the liposome, the resultant structure would have been different from the structure of the reacting liposome and the reacting LNP by themselves. The specification then discloses that particle size, polydispersity index, and zeta potential are measured, but does not disclose what measurements were obtained.
The specification then discloses results of a dose optimization study on page 9, Example 5, with results provided in figure 2. However, the chemical identity of the liposome lipids, the LNP lipids, the amounts of ingredients, or characterization of the product thus formed does not appear to have been disclosed in the specification with respect to Example 5. As such, the relevance of this example regarding showing that a particular subject matter is enabled is unclear to the examiner.
In example 6 of the specification, this example appears to describe LNPs formed from DOTAP, DSPC, cholesterol, and PEG2000 along with nucleic acid is provided, as of pages 9-10 of the specification. The above-indicated formulation appears to be a LNP. This LNP is then combined with a liposome designated as “CT-02.” The term “CT-02” does not appear to be a term of art. As such, the specification does not appear to adequately describe the liposome with which the lipid nanoparticle was combined. As such, Example 6, as well as Examples 7-8 of the specification which further depend on Example 6, fail to show that the claimed invention is properly enabled.
As such, the specification provides no direction or guidance for practicing the claimed invention in its “full scope”.
4. The quantity of experimentation necessary (H)
Because of the known unpredictability of the art, and in the absence of experimental evidence, no one skilled in the art would accept the assertion that the instantly claimed method could have operated in a manner that the supramolecular assembly of the mRNA/LNP structure would not have been disrupted and that the composition would have been therapeutically effective, as inferred by the claim and contemplated by the specification. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the claimed invention in its “full scope” a person of ordinary skill in the art would have to engage in undue experimentation, with no reasonable expectation of success.
Allowable Subject Matter
Claim 24 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
As relevant prior art, the examiner cites Schariter et al. (US 2020/0306191 A1), Tenchov et al. (ACS Nano, Vol. 15, 2021, pages 16982-17015 and supplemental pages 1-10), and Domingues et al. (Langmuir, Vol. 26(13), 2010, pages 11077-11084), which were cited above. Schariter is drawn to lipid nanoparticles (LNPs) comprising mRNA. Tenchov and Domingues are drawn to giant unilamellar liposomes, which can be used in place of cells for the purposes of testing mRNA LNPs such as those of Schariter.
Even if, purely en arguendo, the skilled artisan would have been motivated to have used sonication to have prepared the lipid nanoparticle comprising mRNA (e.g. such as that of Schariter), this would not have been sufficient to render the instant claims obvious. This is because claim 24 recites sonication of the liposome, not the lipid nanoparticle, and Schariter is relied upon to teach the lipid nanoparticle rather than the liposome. In the above-applied obviousness rejection, the examiner cited Tenchov to teach forming a giant unilamellar liposome that was intended to read on the step of “forming liposomes” of claim 20. The skilled artisan would have understood that sonication is used in the art to reduce liposome sizes. As such, the skilled artisan would not have been motivated to have sonicated a giant liposome because of the expectation that by doing so, the giant liposome would have been broken into smaller liposomes and would no longer have been giant.
As such, the skilled artisan would have expected that sonicating the liposomes of Tenchov and/or Domingues prior to combination with the mRNA LNP of Schariter would have resulted in the liposomes of Tenchov and Domingues no longer having been giant because sonication would have reduced their size. This modification would have rendered Tenchov and Domingues unsuitable for their intended purpose which necessitates said liposome being giant. A proposed modification cannot render the prior art unsatisfactory for its intended purpose, and sonication of the giant liposomes of Tenchov and Domingues would have rendered that liposome not to be giant and no longer to be a good model for a cell. See MPEP 2143.01(V).
Additionally, the rationale in the above-applied rejection for lack of enablement does not apply to claim 24 because claim 24 requires neither therapeutic effectiveness (as is required by claim 32) or a lack of disruption of the supramolecular assembly (as required by claim 22), and it is on this basis that claims 24 and 32 are rejected for lack of enablement.
The examiner notes that the prior art, including the Schariter reference applied above, teaches a method that occurs by the following steps and is referred to as either post-insertion or post-addition:
An intermediate lipid nanoparticle formulation, optionally including mRNA, is prepared. This intermediate particle includes ionizable and/or cationic lipid, helper lipid such as phosphatidylcholine, and structural lipid such as cholesterol. However, this intermediate lipid nanoparticle lacks PEGylated lipid.
The intermediate lipid nanoparticle is subsequently combined with PEGylated lipid to form a final lipid nanoparticle.
The examiner takes the position that the method described above does NOT read on the claimed method. This is because in the method above, PEGylated lipid would have been in the form of a micelle rather than a liposome prior to incorporation with the lipid nanoparticle. Support for this position is provided by Iden et al. (Biochimica et Biophysica Acta, Vol. 1513, 2001, pages 207-216). Iden et al. (hereafter referred to as Iden) is drawn to immunoliposomes prepared by a post-insertion method, as of Iden, page 207, title and abstract. Uster teaches the following as of page 208, left column, relevant text reproduced below with annotation by the examiner.
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Even if, purely en arguendo, the “immunoliposome” prior to post-insertion is considered to be a lipid nanoparticle comprising RNA, it is still the case that the PEG-lipid derivative prior to post-insertion is a micelle rather than a liposome. The examiner clarifies that a micelle differs from a liposome because a micelle has a non-polar core whereas a liposome has an aqueous core.
There would have been no reasonable expectation that a micelle and a liposome could have been successfully interconverted because certain lipids naturally exist in a liposome (i.e. bilayer or vesicle) phase, whereas other lipids naturally exist in a micelle phase, and this is based upon the physical and chemical properties of the lipid. Support for this position is obtained by Israelachvili et al. (Quarterly Reviews of Biophysics, Vol. 13(2), 1980, pages 121-200). Israelachvili et al. (hereafter referred to as Israelachvili) teaches the following on page 158, relevant figure reproduced below.
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The above-reproduced table indicates that certain lipids naturally exist in micellar structures whereas other lipids naturally exist in liposome structures (which Israelachvili refers to as a flexible bilayer structure). According to Israelachvili, the type of structure adopted by a lipid depends on the chemical properties of the lipid. As such, there would have been no reasonable expectation that the PEG-lipid micelle of Iden could have been interconverted to a liposome and no motivation for the skilled artisan to have done this.
Conclusion
Less than all claims are in condition for allowance.
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ISAAC . SHOMER
Primary Examiner
Art Unit 1612
/ISAAC SHOMER/ Primary Examiner, Art Unit 1612