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 .
Claim Rejections - 35 USC § 102
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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 3, 9–10, 13–16, 18–20, 23–25, and 29–33 are rejected under 35 U.S.C. 102(a)(2) as anticipated by Benenato et al., U.S. Patent Publication No. 2023/0000773 (“BENENATO”).
BENENATO is based on PCT/US2020/051629, filed September 18, 2020, and names an inventive entity different from that of the present application. BENENATO was therefore effectively filed before the March 24, 2021 effective filing date of the claimed invention and qualifies under 35 U.S.C. 102(a)(2), subject to the exceptions of 35 U.S.C. 102(b)(2).
Regarding claim 1, BENENATO discloses compounds of Formula A-1 comprising a tertiary amine connected to two ester-containing arms and an R⁴ headgroup. See BENENATO claims 1–2 and paragraphs [0081]–[0089].
The compounds expressly depicted in BENENATO claim 18 include an R′ᵃ ester tail having an alkyl branch encompassed by the claimed Rᵃβ, Rᵃγ, or Rᵃδ alternatives; an R′ᵇ group in which the oxygen-bearing carbon is attached to R² and R³ alkyl chains; the claimed tertiary-amine and diester-arm arrangement; and an R⁴ group encompassed by the claimed —(CH₂)ₙNRTQ or —(CH₂)ₙNRS(O)₂TQ alternatives.
BENENATO teaches that R² and R³ may independently be C₃–₁₄ alkyl or alkenyl and expressly discloses R² and R³ as C₈ alkyl. See paragraphs [0133] and [0143]. BENENATO further discloses R′ chain lengths within the claimed ranges and R as hydrogen. See paragraphs [0136] and [0149]. The individual compounds are disclosed in Table 1 and claim 18. See paragraph [0153]. Accordingly, an expressly disclosed BENENATO species falls within the genus of claim 1.
Regarding claim 3, the methylene spacer lengths in the Formula A-1 compounds expressly depicted in BENENATO claim 18 fall within the claimed m and l ranges of 4, 5, or 6.
Regarding claim 9, BENENATO expressly discloses n as 2, 3, or 4. See BENENATO claim 3 and paragraphs [0107]–[0109].
Regarding claim 10, BENENATO expressly discloses R as hydrogen. See BENENATO claim 5 and paragraph [0149].
Regarding claim 13, BENENATO discloses an R⁴ sulfonamide in which R^SX is (CH₂)p1R^SX1, p1 is 1, and R^SX1 is a five- or six-membered heterocycle. This corresponds to T being a C₁ alkyl linker and Q being a five- or six-membered heterocycle. See BENENATO paragraphs [0091], [0095], and [0098]–[0103].
Regarding claims 14 and 15, BENENATO discloses heterocyclic Q groups substituted with one or more groups selected from oxo, amino, C₁–₆ alkylamino, C₁–₆ alkyl, and C₁–₆ alkoxy. See BENENATO claim 1 and paragraphs [0096] and [0116]–[0120]. Express examples of the substituted heterocyclic headgroups are depicted in BENENATO claim 18 and Table 1.
Regarding claim 16, BENENATO claim 17 expressly depicts R⁴ groups recited in claim 16. Additional R⁴ structures falling within claim 16 are depicted in BENENATO claim 18 and Table 1. See BENENATO claims 17–18 and paragraphs [0125]–[0132] and [0153].
Regarding claim 18, BENENATO discloses an empty LNP comprising a Formula A-1 compound, a phospholipid, a structural lipid, and a PEG lipid. See BENENATO claim 19 and paragraphs [0217], [0318], and [0319].
Regarding claim 19, BENENATO discloses an LNP comprising approximately 40–60 mol% of the ionizable lipid, 0–20 mol% phospholipid, 30–50 mol% structural lipid, and 0–5 mol% PEG lipid. See BENENATO claim 20 and paragraph [0325].
Regarding claim 20, BENENATO discloses the recited phospholipid alternatives, including DSPC and the phospholipids listed in BENENATO claim 21. See BENENATO claim 21 and paragraphs [0217] and [0326]–[0336].
Regarding claim 23, BENENATO discloses PEG lipids of Formula PL-II and Formula PL-III. See paragraphs [0240]–[0249] and [0251].
Regarding claim 24, BENENATO expressly discloses PEG₂k-DMG and PEG-1. See BENENATO claim 24 and paragraphs [0222]–[0224], [0248], and [0251].
Regarding claim 25, BENENATO discloses a loaded LNP comprising the previously described lipid components and one or more therapeutic or prophylactic agents. See BENENATO claim 25 and paragraphs [0253] and [0320].
Regarding claim 29, BENENATO discloses a pharmaceutical composition comprising the loaded LNP and a pharmaceutically acceptable carrier or excipient. See BENENATO claim 29 and paragraph [0309].
Regarding claim 30, BENENATO discloses administering a loaded LNP to a subject to deliver a therapeutic or prophylactic agent to a cell within the subject. See BENENATO claim 30 and paragraphs [0378]–[0380].
Regarding claim 31, BENENATO expressly discloses specifically delivering a therapeutic or prophylactic agent to an organ of a subject. See BENENATO claim 31 and paragraphs [0381]–[0383].
Regarding claim 32, BENENATO discloses administering an mRNA-loaded LNP to produce a polypeptide of interest in a cell within a subject. See BENENATO claim 32 and paragraphs [0387]–[0389].
Regarding claim 33, BENENATO discloses administering a loaded LNP to a subject to treat a disease or disorder. The disclosed treatment alternative falls within the claimed “treating or preventing” alternative. See BENENATO claim 33 and paragraphs [0390]–[0392].
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (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.
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.
Claims 2, 8, and 17 are rejected under 35 U.S.C. 103 as unpatentable over Benenato et al., U.S. Patent Application Publication No. 2023/0286903 (“BENENATO (US’903)”), in view of Benenato et al., U.S. Patent Application Publication No. 2023/0000773 (“BENENATO (US’773)”).
Regarding claim 2, BENENATO (US’903)0 discloses the claimed central tertiary amine and two biodegradable ester arms and further discloses the gamma-branched tail configurations of Formula I. See BENENATO (US’903)0 Formulae 1-1, I-a, A-c, and B-c; claims 3–4; and paragraphs [0223]–[0230].
BENENATO (US’903)0 teaches gamma-position C₂–₆ alkyl branches; R′ groups including C₃–₅ alkyl; R² and R³ independently selected from C₁–₁₄ alkyl and C₂–₁₄ alkenyl, including R²=R³=C₈ alkyl; and ester-arm spacer lengths within the claimed ranges. See BENENATO (US’903)0 paragraphs [0236]–[0247] and [0250]. BENENATO (US’903)0 claim 13 and Table 1 expressly depict compounds having the claimed tail frameworks. See paragraph [0258].
BENENATO (US’903)0 differs from claim 2 in that its expressly depicted compounds use a hydroxyethyl R⁴ group rather than the claimed heterocyclic or sulfonamide R⁴ headgroups.
BENENATO (US’773) discloses the missing R⁴ headgroups on the same type of tertiary-amine, diester ionizable-lipid scaffold. BENENATO (US’773) teaches n as 2, 3, or 4; R as hydrogen; sulfonamide headgroups containing methylene-linked five- or six-membered heterocycles; and amino-substituted thiadiazole and oxadiazole headgroups. See BENENATO (US’773) claims 3–17 and paragraphs [0089], [0091], [0095]–[0109], and [0111]–[0120].
It would have been obvious to substitute one of BENENATO (US’773)’s disclosed R⁴ headgroups for the hydroxyethyl R⁴ group of BENENATO (US’903)0 to provide an alternative ionizable lipid for intracellular delivery. BENENATO (US’903)0 and BENENATO (US’773) disclose the same central tertiary-amine/biodegradable-diester architecture and use the resulting lipids in LNPs for intracellular delivery. See BENENATO (US’903)0 paragraphs [0078]–[0079] and [0259] and BENENATO (US’773) paragraphs [0035]–[0036], [0217], and [0253].
One of ordinary skill would have had a reasonable expectation that the resulting lipid could be incorporated into an LNP because BENENATO (US’903)0 demonstrates LNP formation using the claimed branched-tail scaffold, while BENENATO (US’773) demonstrates LNP formation using the claimed R⁴ headgroups. The claims do not require a particular improvement in potency, organ distribution, or therapeutic index.
Regarding claim 8, BENENATO (US’903)0 expressly discloses the gamma-branched tail arrangements corresponding to Formulae I-A1 through I-A4. See BENENATO (US’903)0 claims 4 and 13, paragraphs [0223]–[0250] and [0258], and the expressly depicted compounds on WO pages 255–256. BENENATO (US’773) supplies the claimed R⁴ headgroups. Claim 8 therefore would have been obvious for the reasons stated for claim 2.
Regarding claim 17, at least the first expressly listed compound of claim 17 combines the branched-tail scaffold depicted in BENENATO (US’903)0 claim 13 with the aminothiadiazole R⁴ headgroup depicted in BENENATO (US’773) claim 17. The second listed compound similarly combines the same BENENATO (US’903)0 tail scaffold with the second R⁴ headgroup of BENENATO (US’773) claim 17. Because at least one expressly recited alternative would have been obvious, claim 17 is unpatentable over BENENATO (US’903)0 in view of BENENATO (US’773).
Claim Rejections - 35 USC § 112
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 31 and 33 is/are rejected under 35 U.S.C. § 112(a) because the specification, while being enabling for certain methods employing lipid nanoparticles comprising a lipid according to Formula (I-A1), particularly LNP-mediated delivery of mRNA and expression of an encoded polypeptide, does not reasonably provide enablement commensurate in scope with the methods presently claimed.
Claim 31
Claim 31 is rejected under 35 U.S.C. § 112(a) as failing to comply with the enablement requirement.
Claim 31 recites a method of “specifically delivering a therapeutic and/or prophylactic agent to an organ of a subject” by administering the loaded LNP of claim 25. The claim does not limit the organ, therapeutic or prophylactic agent, targeting mechanism, lipid composition within the elected Formula (I-A1) species, helper-lipid composition, administration route, dose, or other formulation parameters necessary to obtain the recited organ-specific delivery.
The specification provides substantial disclosure concerning general delivery. Paragraph [00298] teaches delivery of a protein, cytotoxic agent, radioactive ion, chemotherapeutic agent, or nucleic acid to a mammalian cell or organ. Paragraph [00299] states that an LNP may be specifically delivered to the liver, kidney, spleen, or lung and describes preferential expression in a targeted tissue.
The specification also defines “specifically delivering” at ¶ [0063] as delivering more therapeutic and/or prophylactic agent to a target tissue than to an off-target tissue, including exemplary differences of at least about 1.5-fold through 10-fold or more. The disclosure gives kidney-versus-liver/spleen targeting as an example.
However, these disclosures do not provide a general method by which a skilled artisan can obtain the required specific delivery to an arbitrary organ over the full scope of claim 31. Rather, the disclosure indicates that nanoparticle performance depends materially upon formulation variables. Paragraph [00422] states that the nanoparticles can be optimized according to the selected Formula (I-A1) lipid, additional lipids, lipid amounts, and lipid-to-payload ratio. Paragraph [00424] further reports that the choice of lipid “dramatically affects” particle size, PDI, and encapsulation efficiency.
The working examples are substantially narrower than claim 31. In Example 3, ¶¶ [00425]-[00426], LNPs comprising DSPC, cholesterol, PL-II, a disclosed ionizable lipid, and hEPO mRNA were intravenously administered to mice, and serum hEPO expression was measured six hours after administration. The particles exhibited approximately 92-98% encapsulation efficiency and demonstrated effective mRNA delivery. Example 4, ¶ [00427], evaluates uptake and GFP expression in cultured HeLa cells. Neither example establishes preferential organ distribution or specific delivery to the unrestricted range of organs encompassed by claim 31.
Thus, the specification is reasonably enabling for preparation and administration of Formula (I-A1)-containing LNPs for cellular delivery of mRNA and subsequent expression of encoded protein, but the disclosure does not reasonably enable the substantially broader result of specifically delivering an unrestricted therapeutic or prophylactic agent to an unrestricted organ.
With respect to the Wands factors, the breadth of claim 31 is substantial; organ-specific LNP delivery is dependent upon interacting biological and formulation variables; the disclosure provides only general guidance regarding organ targeting; no working example demonstrates the claimed organ-specific delivery; and obtaining the claimed result throughout its scope would require identifying and testing appropriate combinations of ionizable lipid structure, helper lipids, component ratios, payload, dose, route, and targeting conditions. The required experimentation would therefore amount to more than routine verification of embodiments taught by the specification and would constitute undue experimentation.
Accordingly, the scope of enablement provided by the specification is not commensurate with the scope of claim 31. Claim 31 is therefore rejected.
Claim 33
Claim 33 is rejected under 35 U.S.C. § 112(a) as failing to comply with the enablement requirement.
Claim 33 recites a method of “treating or preventing a disease or disorder in a subject in need thereof” by administering the loaded LNP of claim 25. The claim contains no limitation as to the disease or disorder, therapeutic or prophylactic agent, molecular mechanism, target tissue, dosage, administration route, treatment duration, or therapeutic endpoint. Claim 25 itself broadly permits one or more therapeutic and/or prophylactic agents.
The specification provides guidance regarding certain therapeutic applications. Paragraph [00306] teaches that the disclosed LNPs may be useful for treating or preventing diseases characterized by missing or aberrant protein or polypeptide activity. One disclosed embodiment employs an LNP containing mRNA encoding a missing or aberrant polypeptide, such that translation of the mRNA produces the polypeptide. Paragraph [00306] additionally identifies sepsis, stroke, and myocardial infarction as exemplary acute conditions.
Paragraph [00307] identifies a broad assortment of possible disease categories, including rare diseases, infectious diseases, cancer and proliferative diseases, genetic diseases, autoimmune diseases, diabetes, neurodegenerative diseases, cardiovascular and renovascular diseases, and metabolic diseases. These passages identify contemplated therapeutic fields, but they do not provide operative teachings demonstrating how the Formula (I-A1)-containing LNPs are to treat or prevent every disease or disorder encompassed by claim 33.
The working examples are considerably narrower. Example 3 demonstrates delivery of hEPO mRNA to mice followed by measurement of serum hEPO expression; Example 4 demonstrates cellular uptake and GFP expression in HeLa cells. ¶¶ [00425]-[00427]. Neither example demonstrates treatment or prevention of a disease or disorder or establishes a general relationship by which successful mRNA delivery or protein expression can be extrapolated to therapeutic efficacy across the entire disease genus of claim 33.
Further, the specification recognizes that LNP properties depend upon selection of the ionizable lipid, additional lipids, relative lipid amounts, and lipid-to-payload ratio, and expressly reports that changing the lipid can dramatically affect nanoparticle characteristics. ¶¶ [00422]-[00424]. These variables would necessarily be considered together with the identity and biological activity of the therapeutic agent, disease target, administration route, and dose when attempting to achieve the therapeutic result required by claim 33.
The breadth of the claim relative to the disclosure therefore weighs strongly against full-scope enablement. The specification provides meaningful direction concerning mRNA delivery and protein production and describes contemplated treatment of diseases associated with missing or aberrant protein activity, but claim 33 is not limited to those embodiments. Instead, it encompasses treatment or prevention of any disease or disorder using any therapeutic or prophylactic agent encompassed by claim 25.
Given the breadth of the claimed therapeutic result, the biological variability among the encompassed diseases and therapeutic mechanisms, the absence of working examples establishing disease treatment or prevention, the formulation-dependent performance disclosed by applicant, and the amount of disease-specific experimentation required to determine an effective payload, formulation, dose, route, target, and treatment regimen, a person of ordinary skill would be required to engage in undue experimentation to practice the full scope of claim 33.
The fact that the specification identifies numerous diseases that might be treated does not by itself establish enablement of the entire genus. Under MPEP § 2164.08, the relevant question is whether everything falling within the scope of the claim can be made and used without undue experimentation. Further, Amgen confirms that the extent of the enabling disclosure must correspond to the breadth of the monopoly sought; the more broadly an invention is claimed, the more must be enabled.
Accordingly, the specification is not enabling commensurate in scope with claim 31 and claim 33 is rejected under 35 U.S.C. § 112(a).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DEBORAH D CARR whose telephone number is (571)272-0637. The examiner can normally be reached Monday-Friday (10:30 am -6:30 pm).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Renee Claytor can be reached at 572-272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/DEBORAH D CARR/Primary Examiner, Art Unit 1691
Prosecution Insights