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 1-21 are pending in this office action. Claim 22 is cancelled. All pending claims are under examination in this application.
Priority
The current application was filed on November 28, 2023 is a 371 of PCT/CA2022/050835 filed May 26, 2022 which, in turn claims domestic priority to provisional patent applications 63/214,977, 63/214,995, and 63/194,471 filed June 25, 2021, June 25, 2021 and May 28, 2021, respectively.
Information Disclosure Statement
Receipt of the Information Disclosure Statement filed on May 6, 2024 is acknowledged. A signed copy of the document is attached to this office action.
Claim Objections
Claim 10 is objected to because of the following informality:
Claim 10 please insert the text “1-5 synthetic steps”.
Appropriate correction is required.
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 1-21 are rejected under 35 U.S.C. 103 as being unpatentable over Manoharan et al. (US2012/0095075A1) in view of Akinc et al. (WO2010/088537A2), Manoharan et al. (WO2009/132131A1), and Yoshida et al. (Tetrahedron Letters, 1997).
[The Examiner is going to introduce each new reference and then combine them where appropriate to reject the instant claims.]
1. Manoharan et al.
Manoharan et al. is considered the closest prior art to the present invention as it teaches novel lipids and compositions for the delivery of therapeutics (see title). In addition, Manoharan et al. disclose that the present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structure: (see abstract).
PNG
media_image1.png
200
400
media_image1.png
Greyscale
2. Akinc et al.
Akinc et al. teach improved lipid formulation (see title). Furthermore, Akinc et al. disclose that the invention features an improved lipid formulation comprising a cationic lipid of formula (A), a neutral lipid, a sterol and a PEG or PEG-modified lipid, where R1 and R2 are independently alkyl, alkenyl or alkynyl, each can be optionally substituted, and R3 and R4 are independently lower alkyl or R3 and R4 can be taken together to form an optionally substituted heterocyclic ring. In one embodiment, R1 and R2 are independently selected from oleoyl, pamitoyl, steroyl, linoleyl and R3 and R4 are methyl. Also disclosed are targeting lipids, and specific lipid formulations comprising such targeting lipids (see abstract).
PNG
media_image2.png
218
243
media_image2.png
Greyscale
4. Manoharan et al. ‘131
Manoharan et al. ‘131 teach amino lipid based improved lipid formulation (see title). Additionally, Manoharan et al. ‘131 disclose that the present invention provides compositions and methods for the delivery of therapeutic agents to cells. In particular, these include novel lipids and nucleic acid-lipid particles that provide efficient encapsulation of nucleic acids and efficient delivery of the encapsulated nucleic acid to cells in vivo. The compositions of the present invention are highly potent, thereby allowing effective knock-down of specific target protein at relatively low doses. In addition, the compositions and methods of the present invention are less toxic and provide a greater therapeutic index compared to compositions and methods previously known in the art. Formulae (I), (II), (III), (IV) (see abstract).
PNG
media_image3.png
200
400
media_image3.png
Greyscale
3. Yoshida et al.
Yoshida et al. teach TiCl4/Bu3N/(catalytic TMSOTf): efficient agent for direct aldol addition and Claisen condensation (see title). Also, Yoshida et al. disclose that among the numerous elaborated aldol-type addition reactions, TiCl4 famine-mediated systems (Evans protocol) have great merits in their efficiency: direct (straightforward) procedure, operational simplicity and accessibility, mild conditions, and its high level of diastereo- and enantioselective version. The amine base employed in conjunction with TiCl4 has been limited to Et3N, i-Pr2NEt, and TMEDA. In order to brush up this reaction we directed our attention to the use of another amine whose method was guided by the fundamental aldol addition of ketones and aldehydes. Consequently, an improved TiCl4/Bu3N reagent demonstrates several significant advantages in enhanced syn-stereoselectivities, especially, in the performance of the cross coupling between two different ketones. To our knowledge, the general method for this ketone-ketone direct cross coupling is limited to the Sn(OTf)2/amine mediated aldol additions. In addition, we extended the present method to the direct Claisen condensation between methyl esters promoted by TiCl4/Bu3N with catalytic TMSOTf (see abstract).
Combination of Manoharan et al., Akinc et al., Manoharan et al. ‘131 and Yoshida et al.
Regarding instant claim 1, Manoharan et al., Akinc et al., Manoharan et al. ‘131 and Yoshida et al. teach a method for producing an ionizable lipid. The necessary citations of Manoharan et al., Akinc et al., Manoharan et al. ‘131 and Yoishida et al. that pertain to instant claim 1 are presented in Table I.
Table I
Instant Claim 1
Manoharan et al., Akinc et al., Manoharan et al. ‘131 and Yoshida et al. Citations
PNG
media_image4.png
200
400
media_image4.png
Greyscale
Manoharan et al. disclose the preparation of ionizable lipids (see title and abstract; also see Examples within Manoharan et al.).
Manoharan et al., Akinc et al., and Manoharan et al. ‘131 disclose a ketone fatty acid intermediates en route to the final lipids [see Examples (ketones 7 and 31) within Manoharan et al.], [see Examples (ketone 7) within Akinc et al.], and [see Examples (ketone 7 and 15) within Manoharan et al. ‘131].
An alternative synthetic route to the desired ketone would be to proceed from the commercial fatty ester (eg. methyl linoleate, methyl stearate, etc.) reacting the fatty ester in a Claisen condensation to obtain the b-ketoester. This would be followed by saponification and decarboxylation to afford the ketone.
As a precedent for the Claisen condensation reaction, Yoshida et al. disclose the TiCl4 catalyst to perform this organic transformation (see title and abstract within Yoshida et al.). Although Yoshida et al. do not disclose specific Examples employing fatty esters, a skilled artisan (POSITA; person having ordinary skill in the art) could use the Yoshida et al. disclosure as a template for reaction with fatty esters. Therefore, modifying the ionizable lipid synthetic pathway.
Additionally, Yoshida et al. disclose Claisen condensation conditions in toluene at RT for 2 h or toluene at 60 °C for 5-6 h (see Table 2 within Yoshida et al.).
The appropriate R groups are commercially available for the fatty esters.
PNG
media_image5.png
200
400
media_image5.png
Greyscale
The resulting Claisen condensation product would afford the general structure of b-ketoesters.
PNG
media_image6.png
200
400
media_image6.png
Greyscale
With the b-ketoester in hand a well-known two-step synthetic transformation would afford the ketone:
Saponification
Decarboxylation
A skilled artisan (POSITA) would carry out these reactions under routine experimental conditions.
Therefore, a skilled artisan (POSITA) would consult the disclosures of Manoharan et al., Akinc et al., Manoharan et al. ‘131 and Yoshida et al. to teach all the elements of instant 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 Manoharan et al., Akinc et al., Manoharan et al. ‘131 and Yoshida et al.
Regarding instant claims 2 and 3, Manoharan et al., Akinc et al., Manoharan et al. ‘131 and Yoshida et al. teach wherein the ketone is subjected to the reduction in step (iv) to produce the alcohol. Manoharan et al., Akinc et al., Manoharan et al. ‘131 disclose the fatty alcohol intermediates (see page 96, Scheme 5 within Manoharan et al. ‘131) (see page 102, step 1a(i) within Akinc et al.) (see Example 2, Scheme 2 within Manoharan et al.). As stated within instant claim 1, modification of the synthetic pathway via Claisen condensation would be routine for a synthetic organic chemist. A skilled artisan (POSITA) would be able to reduce the ketone under routine experimental conditions with a mild reducing agent such as sodium borohydride.
Regarding instant claim 4, Manoharan et al., Akinc et al., Manoharan et al. ‘131 and Yoishida et al. teach wherein the catalyst is TiC4. Yoshida et al. disclose a Claisen condensation set of reaction conditions using titanium (IV) tetrachloride (see instant claim 1).
Regarding instant claims 5 through 8, Manoharan et al., Akinc et al., Manoharan et al. ‘131 and Yoshida et al. teach wherein in the hydrolysis and decarboxylation, the base is an aqueous strong base and the acid is an aqueous strong acid, and wherein the aqueous strong acid is added to a resultant solution formed upon an addition of the aqueous strong base to the ketoester. A skilled artisan (POSITA) would be able to saponify the b-ketoester under routine experimental conditions with a aqueous base such as sodium hydroxide. This would be followed by decarbonylation with a strong acid such as hydrochloric acid. Ideally, a skilled artisan (POSITA) could perform these two-steps in one reaction vessel.
Regarding instant claim 9, Manoharan et al., Akinc et al., Manoharan et al. ‘131 and Yoshida et al. teach wherein the fatty ester of step (ii) step (i) is obtained from a synthesis scheme comprising a step of ozonolysis to cleave a double bond in an alkyl chain of a precursor fatty ester to produce an aldehyde derivative of the precursor fatty ester. Another common transformation within synthetic organic chemistry is the ozonolysis to cleave a double bond and afford a terminal aldehyde. A skilled artisan (POSITA) would be able to perform ozonolysis on the alkene under routine experimental conditions.
Regarding instant claim 10, Manoharan et al., Akinc et al., Manoharan et al. ‘131 and Yoshida et al. teach wherein the one or more steps resulting in an addition of an ionizable head group moiety to the ketone or alcohol comprises 1 to 5 steps. Manoharan et al. disclose the addition of the ionizable head group moiety to the ketone or alcohol within 1 to 5 steps (see Examples 9-10 and 68 within Manoharan et al.).
Regarding instant claim 11, Manoharan et al., Akinc et al., Manoharan et al. ‘131 and Yoshida et al. teach wherein the ionizable lipid produced in step (iv) comprises a linker region. Manoharan et al. disclose a linker region between the fatty acid and the ionizable group (see Examples 9-10 within Manoharan et al.).
Regarding instant claim 12, Manoharan et al., Akinc et al., Manoharan et al. ‘131 and Yoshida et al. teach wherein the fatty ester is a methyl ester or ethyl ester. Lower alkyl esters such as methyl and ethyl are the most common commercial materials available to a skilled artisan (POSITA).
Regarding instant claim 13, Manoharan et al., Akinc et al., Manoharan et al. ‘131 and Yoshida et al. teach wherein the fatty ester is a methyl ester selected from methyl linoleate, methyl linolenate, methyl myristoleate, methyl palmitoleate, methyl myristate, methyl palmitate, methyl stearate, methyl 9-(octylthio )methyl)thio )nonanoate and methyl 9,9-bis(octylthio)nonanoate. The fatty ester methyl stearate is commercial and would be available to a skilled artisan (POSITA).
Regarding instant claim 14, Manoharan et al., Akinc et al., Manoharan et al. ‘131 and Yoshida et al. teach further comprising an addition of an R3 alkyl group to the ketoester prior to the hydrolysis and decarboxylation of the ketoester. A skilled artisan (POSITA) could select a reagent suitable for the ionizable lipid based on synthetic or commercially available starting materials.
Regarding instant claim 15, Manoharan et al., Akinc et al., Manoharan et al. ‘131 and Yoshida et al. teach a method for preparing a drug delivery vehicle comprising (a) producing an ionizable lipid using the method of instant claim 1; and (b) formulating the ionizable lipid so produced in the drug delivery vehicle. Please see the discussion and citations within instant claim 1 for the necessary rejection text. Akinc et al. disclose a mixture of lipids comprising the ionizable lipid, DSPC, cholesterol, and PEG-DMG (see Example 10 within Akinc et al.) which can be formulated with the therapeutic agent of choice.
Regarding instant claim 16, Manoharan et al., Akinc et al., Manoharan et al. ‘131 and Yoshida et al. teach wherein the drug delivery vehicle is a lipid nanoparticle. Akinc et al. disclose, for example, ApoE binding to neutral liposomes particularly LNP05 can dramatically enhance the cellular uptake of these lipid nanoparticles (see page 123, paragraph 2 within Akinc et al.).
Regarding instant claim 17, Manoharan et al., Akinc et al., Manoharan et al. ‘131 and Yoshida et al. teach wherein the step of formulating comprises admixing a therapeutic agent or prodrug, with the ionizable lipid. Akinic et al. disclose formulation of lipid(s) further comprising a therapeutic agent inclusive of a prodrug (see claim 11 and pages 35 and 41-50 within Akinc et al.).
Regarding instant claim 18, Manoharan et al., Akinc et al., Manoharan et al. ‘131 and Yoshida et al. teach wherein a nucleic acid, peptide, ribonucleoprotein, or protein is admixed with the ionizable lipid and wherein the drug delivery vehicle comprises the nucleic acid, peptide, ribonucleoprotein or protein. Akinc et al. disclose a variety of therapeutic agents including nucleic acids, peptides, ribonucleoproteins or proteins (see pages 35 and 41-50 within Akinc et al.). These therapeutic agents are encapsulated within the lipid nanoparticle (LNP) which would contain the ionizable lipid (see page 41 paragraph 3 within Akinc et al.).
Regarding instant claim 19, Manoharan et al., Akinc et al., Manoharan et al. ‘131 and Yoshida et al. teach further comprising admixing the therapeutic agent or prodrug with additional lipids. Please see the discussion and citations within instant claims 1 and 15-18 for the necessary rejection text.
Regarding instant claim 20, Manoharan et al., Akinc et al., Manoharan et al. ‘131 and Yoshida et al. teach wherein the additional lipids are structural lipids or a sterol. Please see the discussion and citations within instant claim 15 for the necessary rejection text (cholesterol).
Regarding instant claim 21, Manoharan et al., Akinc et al., Manoharan et al. ‘131 and Yoshida et al. teach wherein the additional lipids are ionizable lipids. Please see the discussion and citations within instant claims 1 and 10 for the necessary rejection text.
Analogous Art
The Manoharan et al., Akinc et al., Manoharan et al. ‘131 and Yoshida et al. references are directed to the same field of endeavor as the instant claims, that is, a method for producing an ionizable lipid as disclosed within instant claim 1.
Obviousness Analysis
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the lipids and LNP disclosed by Manoharan et al., using the teachings of Akinc et al., Manoharan et al. ‘131, and further in light of Yoshida et al. in order to arrive at the subject matter of the instant claims.
The Manoharan et al., Akinc et al., Manoharan et al. ‘131 and Yoshida et al. references all have considerable overlap for the preparation of ionizable lipids. In this instance, Manoharan et al. supplies the preparation of ionizable lipids, Akinc et al., Manoharan et al. ‘131 further supports the Manoharan et al. citation, while Yoshida et al. supplies the alternative synthetic conditions for a Claisen condensation reaction. The Manoharan et al., Akinc et al., and Manoharan et al. ‘131 prepare the ionizable lipids not by using the Claisen condensation to construct the lipid scaffold. However, using the Yoshida et al. reference a skilled artisan could modify the lipid synthesis under routine experimental conditions. All references are directed to the preparation of ionizable lipids and therefore constitute analogous art under MPEP §2141.01(a). A POSITA would have reasonably consulted the four references when seeking to develop a preparation method for ionizable lipids.
Starting with Manoharan et al., the skilled person only had to try the necessary claim limitations disclosed by Akinc et al., Manoharan et al. ‘131 and Yoshida et al. The combination of Manoharan et al., Akinc et al., Manoharan et al. ‘131 and Yoshida et al. would allow one to arrive at the present application without employing inventive skill. This combination of the preparation of ionizable lipids taught by Manoharan et al. along with the use of the necessary claim limitations taught by Akinc et al., Manoharan et al. ‘131 and Yoshida 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 preparation of ionizable lipids disclosed by Manoharan et al. with the use of the necessary claim limitations taught by Akinc et al., Manoharan et al. ‘131 and Yoshida et al. Incorporating the disclosure of Manoharan et al. into the additional lipid preparations taught by Akinc et al., Manoharan et al. ‘131, and the Claisen condensation conditions by Yoshida et al. represents a predictable use of prior art elements according to their established functions, consistent with MPEP §2143 and KSR.
Furthermore, the additional claim limitations taught by Akinc et al., Manoharan et al. ‘131 and Yoshida et al. would have been viewed by a POSITA as routine design optimizations or known modifications for the preparation of ionizable lipids. Implementing these features in Manoharan et al.’s ionizable lipid preparation would not require more than ordinary skill or routine experimentation.
Accordingly, the combination of Manoharan et al., supplemented by Akinc et al., Manoharan et al. ‘131 and Yoshida et al. provides all the elements of the claimed invention. The resulting preparation method of ionizable lipids constitutes no more than the predictable outcome of combining familiar prior art components, and therefore the claimed subject matter would have been obvious to a POSITA prior to the effective filing date of the invention.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN W LIPPERT III whose telephone number is (571)270-0862. The examiner can normally be reached Monday - Thursday 9:00 AM - 5:00 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, Robert A Wax can be reached on 571-272-0623. 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.
/JOHN W LIPPERT III/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615