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 .
Summary
Claims 1-2, 4, 6-14, 16-20, and 22-24 are pending in this office action. Claims 3, 5, 15, and 21 are cancelled. All pending claims are under examination in this application.
Priority
The current application was filed on November 6, 2023 is a 371 of PCT/US2022/028131 filed May 6, 2022, which in turn claims domestic priority to provisional patent application 63/185,535 filed on May 7, 2021.
Information Disclosure Statement
Receipt of the Information Disclosure Statement filed on June 25, 2025 and February 7, 2024 are acknowledged. A signed copy of both documents are attached to this office action.
Claim Objections
Claim 4 is objected to because of the following informality: Please include the full name for the acronym DDAB (N,N-distearyl-N,N-dimethylammonium bromide).
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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, 6-14, 16-20, and 22-24 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “such as” and this renders the claim indefinite because it is not clear if the limitations following the “such as” are part of the claim or not.
Dependent claims 2, 4, 6-14, 16-20, and 22-24 fail to cure the defect of claim 1.
Additionally, claim 17 has the molar ratio range written in a confusing manner. The Applicant is requested to clarify the claim language. For example, the claimed molar ratio range could be written:
x≤20 to x≤55:x≤10 to x≤60: x≤10 to x≤50:x≤1 to x≤2.5
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.
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 non-obviousness.
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.
Claims 1-2, 4, 6-14, 16-20, and 22-24 are rejected under 35 U.S.C. 103 as being unpatentable over Wooster et al. (WO2021/081058A1, published in April 2021) in view of Novobrantseva et al. (WO2020/033791A1), Hajj et al. (Small, 2019), Anderson et al. (US9,227,917B2), and Pierrat et al. (A European Journal-Chemistry, 2013).
[The Examiner is going to introduce each reference and then combine them where appropriate to reject the instant claims.]
1. Wooster et al.
Wooster et al. is considered the closest prior art as it teaches compositions, methods, and uses of messenger RNA (see title). In addition, Wooster et al. disclose that the present invention provides, among other things, methods and compositions for selective degradation of proteins. In some aspects, messenger RNAs (mRNAs) are described that encode a ubiquitin pathway moiety and a binding peptide that binds a target protein, wherein the mRNA is encapsulated within a lipid nanoparticle. Also provided herein are mRNAs that encode at least two binding peptides, wherein a first binding peptide binds a ubiquitin pathway moiety and a second binding peptide binds a target protein, and wherein the mRNA is encapsulated within a lipid nanoparticle. (see abstract).
2. Novobrantseva et al.
Novobrantseva et al. teach oligonucleotide compositions for targeting CCR2 CSFIR and uses thereof (see title). Furthermore, Novobrantseva et al. disclose that the present invention is based, in part, on providing oligonucleotide compositions for targeting CCR2, CSF1R, and/or both CCR2 and CSF1R, as well as methods of use thereof, such as to modulate myeloid-derive cell inflammatory phenotypes and immune responses that are mediated by such cells. (see abstract).
3. Hajj et al.
Hajj et al. teach branched-tail lipid nanoparticles potently deliver mRNA in vivo due to enhanced ionization at endosomal pH (see title). Additionally, Hajj et al. disclose that the potential of mRNA therapeutics will be realized only once safe and effective delivery systems are established. Unfortunately, delivery vehicle development is stymied by an inadequate understanding of how the molecular properties of a vehicle confer efficacy. Here, a small library of lipidoid materials is used to elucidate structure–function relationships and identify a previously unappreciated parameter—lipid nanoparticle surface ionization—that correlates with mRNA delivery efficacy. The two most potent materials of the library, 306O10 and 306Oi10, induce substantial luciferase expression in mice following a single 0.75 mg kg−1 mRNA dose. These lipidoids, which have ten-carbon tails and identical molecular weights, vary only in that the 306O10 tail is straight and the 306Oi10 tail has a one-carbon branch. Remarkably, this small difference in structure conferred a tenfold improvement in 306Oi10 efficacy. The enhanced potency of this branched-tail lipidoid is attributed to its strong surface ionization at the late endosomal pH of 5.0. A secondary lipidoid library confirms that Oi10 materials ionize more strongly and deliver mRNA more potently than lipidoids containing linear tails. Together, these data highlight the exquisite control that lipid chemistry exerts on the mRNA delivery process and show that branched-tail lipids facilitate protein expression in animals (see abstract).
4. Anderson et al.
Anderson et al. teach amine-containing lipidoids and uses thereof (see title). Further, Anderson et al. disclose that provided herein are lipidoids that may be prepared from the conjugate addition of alkylamines to acrylates. In some embodiments, provided lipidoids are biodegradable and may be used in a variety of drug delivery systems. Given the amino moiety of the lipidoids, they are well-suited for the delivery of polynucleotides, in addition to other agents. Nanoparticles containing the inventive lipidoids and polynucleotides have been prepared and have been shown to be effective in delivering siRNA (see abstract).
5. Pierrat et al.
Pierrat et al. teach phospholipid–detergent conjugates as novel tools for siRNA delivery (see title). Also, Pierrat et al. disclose that one of the potential benefits
of drug delivery systems in medicine is the creation of nanoparticle-based vectors that deliver a therapeutic cargo in sufficient quantity to a target site to enable a selective effect, width of the therapeutic window depending on the toxicity of the vector and the cargo. In this work, we intended to improve the siRNA delivery efficiency of a new kind of nucleic acid carrier, which is the result of the conjugation of the membrane phospholipid 1,2-dioleoylsn-glycero-3-phosphocholine (DOPC) to the membrane-active species Triton X-100 (TX100). We hypothesized that by improving the biodegradability the cytotoxicity of the conjugate might by reduced, whereas its original transfection potential would be tentatively preserved. DOPC was conjugated to Triton X-100 through spacers displaying various resistance to chemical hydrolysis and enzyme degradation. The results obtained through in vitro siRNA delivery experiments showed that the initial phosphoester bond can be replaced with a phospho(alkyl)enecarbonate group with no loss in the transfection activity, whereas the associated cytotoxicity was significantly decreased, as assessed by metabolic activity and membrane integrity measurements.
The toxicity of the conjugates incorporating a phospho(alkyl)enesuccinnate moiety proved even lower but was clearly balanced with a reduction of the siRNA delivery efficiency. Hydrolytic stability and intracellular degradation of the conjugates were investigated by NMR spectroscopy and mass spectrometry. A general trend was that
the more readily degraded conjugates were those with the lower toxicity. Otherwise,
the phosphor(alkyl)enecarbonate conjugates revealed some hemolytic activity, whereas the parent phosphoester did not. The reason why these conjugates behave differently with respect to hemolysis might be a consequence of unusual fusogenic properties and probably reflects the difference in the stability of the conjugates in the environment (see abstract).
Combination of Wooster et al. and Novobrantseva et al.
Regarding instant claim 1, Wooster et al. and Novobrantseva et al. teach a method of delivering a therapeutic agent to a pancreas of a patient. The necessary citations of Wooster et al. and Novobrantseva et al. that pertain to instant claim 1 are presented in Table I.
Table I
Instant Claim 1
Wooster et al. and Novobrantseva et al. Citations
A method of delivering a therapeutic agent to a pancreas of a patient, comprising administering to a patient a composition comprising a lipid-containing particle, such as a lipid nanoparticle, comprising a therapeutic agent, the lipid- containing particle comprising:
Wooster et al. disclose the use of cationic ionizable lipidoids for mRNA delivery (see paragraphs [0007], [0036], and [0235] within Wooster et al.) wherein the mRNA is encapsulated within a lipid nanoparticle (see paragraph [0007] within Wooster et al.)
Novobrantseva et al. disclose siRNA (see page 3, line 3 within Novobrantseva et al.) encapsulated within lipid nanoparticles (see page 114, line 14 within Novobrantseva et al.). Furthermore, Novobrantseva et al. disclose treatment of pancreatic cancer (see page 16, line 16 within Novobrantseva et al.) [delivering the therapeutic agent to the pancreas].
a cationic helper lipid; cholesterol or a derivative thereof; a PEG-based compound; and an ionizable lipidoid.
Wooster et al. disclose a mixture of lipids including an ionizable lipid (lipidoid) which constitutes at least about 5-70%, measured as a mol %, of the total lipid content (see paragraph [0255] within Wooster et al.), a helper lipid, 5-90 mol % such as 1,2-dileoyl-sn-3-phosphoethanolamine (DOPE) (see paragraph [0257] within Wooster et al.), cholesterol-based lipid, 5-40 mol% (see paragraph [0258] within Wooster et al.) and a PEG-lipid, 1-10 mol% (see paragraph [0277] within Wooster et al.) for synthesis of their lipid nanoparticle.
The difference between the formulation of Wooster et al. and the composition of instant claim 1 is the presence of a cationic helper lipid [e.g. 1,2-dioleyloxy-N,N-dimethylaminopropane (DODMA)] instead of a neutral helper lipid (Wooster et al. uses DOPE).
Novobrantseva et al. disclose lipid nanoparticles (LNP) comprising siRNA (see claims 1 and 16-33 within Novobrantseva et al.). The LNP comprises one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids and one or more PEG-modified lipids (see page 117, lines 4-17 within Novobrantseva et al.). The lipidoid C12-200 (see page 124 within Novobrantseva et al.) as well as DODMA (see page 118, line 16 within Novobrantseva et al.) or 1,2-dioleoyl-3-dimethylammonium propane (DODAP) are listed as cationic lipids (see page 118, line 17 within Novobrantseva et al.).
In the light of the Novobrantseva et al. disclosure, the skilled person would be motivated with a reasonable expectation of success to combine cationic lipids with cationic lipidoids within the Wooster et al. LNP.
Therefore, a skilled artisan (POSITA; person of ordinary skill in the art) would combine the teachings of Wooster et al. and Novobrantseva et al. to disclose all of the subject-matter of present claim 1.
The remainder of the instant claims which are either directly or indirectly dependent on claim 1 are taught in full by the combination of Wooster et al. and Novobrantseva et al.
Regarding instant claim 2, Wooster et al. and Novobrantseva et al. teach wherein the lipid particle comprises: from 10 to 50 mole percent (mol%) of the cationic helper lipid; from 10 to 46.5 mol% of the cholesterol or a derivative thereof; from 1.25 to 2.5 mol% of the PEG-based compound; and from 20 to 45 mol% of the ionizable lipidoid. Wooster et al. disclose a mixture of lipids including a ionizable lipid (lipidoid) which constitutes at least about 5-70%, measured as a mol %, of the total lipid content (see paragraph [0255] within Wooster et al.), a helper lipid, 5-90 mol % such as 1,2-dileoyl-sn-3-phosphoethanolamine (DOPE) (see paragraph [0257] within Wooster et al.), cholesterol-based lipid, 5-40 mol% (see paragraph [0258] within Wooster et al.) and a PEG-lipid, 1-10 mol% (see paragraph [0277] within Wooster et al.) for synthesis of their lipid nanoparticle. The difference between the formulation of Wooster et al. and the composition of instant claim 1 is the presence of a cationic helper lipid [e.g. 1,2-dioleyloxy-N,N-dimethylaminopropane (DODMA)] instead of a neutral helper lipid (Wooster et al. uses DOPE). [Furthermore, Wooster et al. disclose use of cholesterol (see paragraph [0262] within Wooster et al.).]
Novobrantseva et al. disclose lipid nanoparticles (LNP) comprising siRNA (see claims 1 and 16-33 within Novobrantseva et al.). The LNP comprises one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids and one or more PEG-modified lipids (see page 117, lines 4-17 within Novobrantseva et al.). The lipidoid C12-200 (see page 124 within Novobrantseva et al.) as well as DODMA (see page 118, line 16 within Novobrantseva et al.) or 1,2-dioleoyl-3-dimethylammonium propane (DODAP) are listed as cationic lipids (see page 118, line 17 within Novobrantseva et al.).
In the light of the Novobrantseva et al. disclosure, the skilled person was motivated with a reasonable expectation of success to combine cationic lipids with cationic lipidoids within the Wooster et al. LNP.
Regarding instant claim 4, Wooster et al. and Novobrantseva et al. teach wherein the cationic helper lipid is either DODAP or DODMA. Novobrantseva et al. disclose both cationic helper lipids, DODAP and DODMA (see page 118, lines 16-17 within Novobrantseva et al.).
Regarding instant claim 8, Wooster et al. and Novobrantseva et al. teach wherein the LNP comprises cholesterol. Wooster et al. disclose cholesterol and cholesterol-based lipids (see paragraph [0262] within Wooster et al.).
Regarding instant claims 11-14, Wooster et al. and Novobrantseva et al. teach wherein the therapeutic agent is anionic or polyanionic and a nucleic acid (RNA). Wooster et al. disclose the encapsulation of an anionic (see PTO-892 NPL U) therapeutic agent, mRNA (see paragraph [see paragraph [0007] within Wooster et al.)
Regarding instant claims 19-20, Wooster et al. and Novobrantseva et al. teach wherein the lipid-containing particle is delivered to the patient orally, intravenously, intraperitoneally, intramuscularly, subcutaneously, or intradermally. Wooster et al. disclose the mRNA is administered intravenously, intradermally, subcutaneously, intrathecally, orally, or by inhalation or nebulization (see paragraph [0043] within Wooster et al.).
Combination of Wooster et al., Novobrantseva et al., and Anderson et al.
Regarding instant claims 6-7, Wooster et al., Novobrantseva et al., and Anderson et al. teach wherein the PEGylated fatty-containing compound is C14-PEG2000 PE. Anderson et al. disclose a C10-C14 PEGylated fatty acid, namely C14-PEG2000 PE (see column 137, line 9 within Anderson et al.).
Combination of Wooster et al., Novobrantseva et al., and Hajj et al.
Regarding instant claims 9-10, Wooster et al., Novobrantseva et al., and Hajj et al. teach wherein the ionizable lipidoid is 306Oi10. Hajj et al. disclose the use of potent branched lipidoid 306Oi10 (see abstract and Figure 1; both within Hajj et al.).
Regarding instant claim 24, Wooster et al., Novobrantseva et al., and Hajj et al. teach wherein the lipid-containing particle comprises: DDAB as the cationic helper lipid; cholesterol; C14-PEG2ooo PE as the PEGylated fatty acid-containing compound; and 3060i10 as the ionizable lipidoid. Novobrantseva et al. disclose the use of the cationic helper lipid DDAB (see page 118, lines 28-29 within Novobrantseva et al.). Wooster et al. disclose use of cholesterol (see paragraph [0262] within Wooster et al.). Anderson et al. disclose the use of the PEGylated fatty acid-containing compound C14-PEG2ooo PE (see instant claims 6-7). Finally, Hajj et al. disclose the ionizable lipidoid 306Oi10 (see instant claims 9-10).
Combination of Wooster et al., Novobrantseva et al., Hajj et al., and Anderson et al.
Regarding instant claims 16-18, Wooster et al., Novobrantseva et al., Hajj et al., and Anderson et al. teach wherein the lipid-containing particle comprises: DOTAP as the cationic helper lipid; cholesterol; C14-PEG2ooo PE as the PEGylated fatty acid-containing compound; and 306Oi10 as the ionizable lipidoid; all lipids or lipidoids at the correct mol percent value. Novobrantseva et al. disclose use of the cationic helper lipid 1,2-dioleoyl-1-3-trimethylammonium propane (DOTAP) (see page 117, line 12 within Novobrantseva et al.). Wooster et al. disclose use of cholesterol (see paragraph [0262] within Wooster et al.). Anderson et al. disclose the use of the PEGylated fatty acid-containing compound C14-PEG2ooo PE (see instant claims 6-7). Finally, Hajj et al. disclose the ionizable lipidoid 306Oi10 (see instant claims 9-10).
Additionally, the correct mol percents of the lipids or lipidoid are disclosed within instant claim 1.
Combination of Wooster et al., Novobrantseva et al., Hajj et al., Anderson et al., and Pierrat et al.
Regarding instant claims 22-23, Wooster et al., Novobrantseva et al., Hajj et al., Anderson et al., and Pierrat et al. teach wherein the EPC is 18:1 EPC. Please see the discussion and citations within instant claims 16-18 for the relevant lipids and lipidoids. Furthermore, Pierrat et al. disclose the use of the cationic helper lipid 18:1 EPC or EDOPC (see Figure 1 within Pierrat et al.).
Analogous Art
The Wooster et al., Novobrantseva et al., Hajj et al., Anderson et al., and Pierrat et al. references are directed to the same field of endeavor as the instant claims, that is, a method of delivering a therapeutic agent to a pancreas of a patient, comprising administering to a patient a composition comprising a lipid-containing particle, such as a lipid nanoparticle, comprising a therapeutic agent.
Obviousness
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the mRNA LNP disclosed by Wooster et al., using the teachings of Novobrantseva et al., Hajj et al., Anderson et al., and Pierrat et al. to incorporate the necessary claim limitations.
Motivation to combine the Wooster et al., Novobrantseva et al., Hajj et al., Anderson et al., and Pierrat et al. references would rely on the common theme of the lipid-nucleic acid complexation and administration within these disclosures. All of these citations have significant overlap regarding this general topic making them analogous art.
Starting with Wooster et al., the skilled person only had to try the necessary claim limitations disclosed by Novobrantseva et al., Hajj et al., Anderson et al., and Pierrat et al. The combination of Wooster et al., Novobrantseva et al., Hajj et al., Anderson et al., and Pierrat et al. would allow one to arrive at the present application without employing inventive skill. This combination of the mRNA LNP taught by Wooster et al. along with the use of the necessary claim limitations taught by Novobrantseva et al., Hajj et al., Anderson et al., and Pierrat et al. would allow a research and development scientist (POSITA) to develop the invention taught in the instant application.
It would have only required routine experimentation to modify the mRNA LNP disclosed by Wooster et al. with the use of the necessary claim limitations taught by Novobrantseva et al., Hajj et al., Anderson et al., and Pierrat et al. This combined modification would have led to an enhanced nucleic acid lipidoid nanoparticle that would be beneficial for patients.
In the context of instant method claims 1-2, 4, 6-14, 16-20, and 22-24 the desired purpose defines an effect that arises from and is implicit in the method step(s). Thus, where the purpose is limited to stating a technical effect that inevitably occurs during the performance of the claimed method step(s), and is therefore inherent in that/those step(s), that technical effect is not limiting to the subject-matter of the claim. Thus, the present method claim, defining the application/use of the composition according to the prior art, and defining its purpose as "use", is anticipated by any document of the state of the art describing a method of application/use although not mentioning this specific use.
Conclusion
No claims are allowed.
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/JOHN W LIPPERT III/Examiner, Art Unit 1615 /Robert A Wax/Supervisory Patent Examiner, Art Unit 1615