DETAILED ACTION
Status of the Application
Receipt is acknowledged of Applicants’ Request for Continued Examination (RCE), Amendments and Remarks, filed 4 September 2026, in the matter of Application N° 18/422,810. Said documents have been entered on the record. The Examiner further acknowledges the following:
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicants’ submission filed on 4 September 2026 has been entered.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 2 and 3 have been canceled. No claims have been added.
Claims 1, 6-9, 11-15, 18, and 20 have been amended. The primary amendments made to the claims add the phrase “one or more” to the recited components in order to overcome the previously raised issues under 35 USC 112. Additional amendments correct grammar and typographical mistakes.
No new matter has been added.
Thus, claims 1, 4-20, and 53 now represent all claims currently under consideration.
Information Disclosure Statement
One new Information Disclosure Statement (IDS) filed 4 September 2026 is acknowledged and has been considered.
Withdrawn Rejections
Rejections under 35 USC 112
Applicants’ amendments to the claims are sufficient in overcoming the previously raised issues under paragraphs (b) and (d) of the statute. Said rejections are withdrawn.
Rejections under Nonstatutory Double Patenting
Applicants’ amendment to the claims removing DOPE as a species of cationic lipid is sufficient in overcoming the previously raised double patenting issue. Said rejections are withdrawn.
Rejections under 35 USC 103
Applicants’ amendment to the claims removing DOPE as a species of cationic lipid is sufficient in overcoming the previously raised obviousness rejection. Said rejection is withdrawn.
Drawings
The drawings are objected to because Figure 6 is not entirely clear in the content being shown. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Maintained Rejections
The following rejections are maintained from the previous Office Correspondence dated 4 May 2026 since the art that was previously cited continues to read on the amended and previously recited limitations.
Claim Rejections - 35 USC §103
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the Examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicants are 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, 6, 7, 11, 16, 19, 20, and 53 are rejected under 35 U.S.C. 103 as being unpatentable over Luo et al. (US Pre-Grant Publication Nº 2013/0165636 A1). [emphasis added to reflect newly canceled claims]
The limitations of the instantly claimed invention are directed to a nanolipoprotein particle comprising:
a membrane forming lipid;
a cationic lipid; and
a scaffold protein;
wherein the membrane forming lipid and the cationic lipid are arranged in a membrane forming lipid bilayer stabilized by the scaffold protein.
Luo discloses a “nanodisc” comprising a membrane scaffold protein, a telodendrimer, and a lipid (see e.g., Abstract claim 1).
The “nanodisc” is considered to disclose the recited nanolipoprotein particle structure as defined in ¶[0003]. Therein, nanolipoprotein particles (or NLPs) are defined as being nanoscale (6-30 nm), discoidal patches of lipid bilayer stabilized by peripheral scaffold.
The lipid is further defined by the reference as being selected from such lipids as a phospholipid, a cholesterol, a phosphatidylcholine, and other lipids such as DPPC, DMPC, MPPC, DSPC, DSPE, DPPE, DSPG, DPPG, MPPG, and cholesterol (see e.g., claims 7-9 and ¶[0058]). Paragraphs [0059], [0060], and [0072] all teach that combinations of lipids may be used in the formation of the NLPs.
DMPC is disclosed in claim 9, thereby teaching the limitations of the recited species of membrane-forming lipid.
Paragraph [0059] additionally teaches that “[a]ny suitable combination of lipids can be used to provide the nanodiscs of the invention. The lipid compositions can be tailored to affect characteristics such as leakage rates, stability, particle size, zeta potential, protein binding, in vivo circulation, and/or accumulation in tissues or organs. For example, negatively or positively lipids, such as DSPG and/or DOTAP, can be included to affect the surface charge of a nanodisc. The lipid compositions can include about ten or fewer types of lipids, or about five or fewer types of lipids, or about three or fewer types of lipids. In some embodiments, the lipid includes at least two different lipids. The molar percentage (mol %) of a specific type of lipid present can be from about 0% to about 10%, from about 10% to about 30%, from about 30% to about 50%, from about 50% to about 70%, from about 70% to about 90%, or from about 90% to 100% of the total lipid present in a nanodisc.” [emphases added]
The membrane scaffold protein is defined by claim 2 as being apolipoprotein. Apolipoproteins are further defined in ¶[0052] as being selected from apolipoproteins A (including, for example, apo A-1 and apo A-2), B, C, D, E, and H.
The telodendrimers are disclosed a being present in the composition in a 9:1 (w/w) of lipid to telodendrimer (see e.g., claim 15). Thus, the telodendrimer is taught as being present in an amount of up to 10% of the total lipid component of the composition.
Based on the combined teachings of the references, the Examiner submits that a person of ordinary skill in the art would have had a reasonable expectation of success at producing the instantly claimed composition. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, and absent a clear showing of evidence to the contrary.
Response to Arguments
Applicants’ arguments with regard to the rejection of claims 1, 6, 7, 11, 16, 19, 20, and 53 under 35 USC 103(a) as being unpatentable over the teachings of Luo et al. have been fully considered, but they are not persuasive.
Applicants traverse the rejection on the grounds that Luo provides unguided disclosure for “billions, if not trillions of possible theoretical formulations,” none of which provide any motivation to select a subclass of cationic lipids and combine them in the specific range to achieve the function of binding large polynucleotides having a length of 200 bp or higher.
The Examiner, in response, respectfully disagrees and maintains the rejection for the reasons already of record. It is further submitted that Applicants’ acknowledgement of the teachings of Luo are indicative that the compositional elements of the claimed invention remain disclosed.
Regarding the “configured to” functionality of the claimed composition, the Examiner additionally advances that there is no recited structural limitations assigned to delineate exactly what structure is meant to provide the alleged binding function. The only structures presented in the claimed invention are a nanolipoprotein particle and that the lipids are arranged as a discoidal membrane forming bilayer stabilized by the one or more scaffold proteins. The Examiner respectfully maintains that this “configuration” is disclosed in ¶[0003] of the reference.
Regarding the compositional elements of the claimed invention, the Examiner maintains that the membrane scaffold protein and at least one lipid (i.e., membrane forming lipid) are both disclosed in the claims of the reference, with claim 9 disclosing a preference for DMPC.
The disclosure of claim 7 is acknowledged. However, the disclosures of ¶[0054], ¶[0057], and ¶[0059] disclose that the lipid component may be defined by one or more lipids. Paragraph [0057] provides disclosure that meets the cationic limitations of claims 1 and 6, while ¶[0059] also reiterates that more than one type of lipid is combined. A combination of negative and positive lipid are exemplified in the passage which is considered to minimally convey to the skilled artisan that potential binding charge of the NLP can be modified as desired. The molar percentage (mol %) of any one lipid may be selected from disclosed ranges such as 10-30 mol%, which the Examiner notes is a range that anticipates the recited range. However, as it is applied to any of the suitable lipids within the practiced composition, the Examiner acknowledges that Luo does not expressly disclose one or more cationic lipids be used in such an amount, but the reference does teach and suggest it.
Thus, Applicants’ remarks traversing the rejection on these grounds remain unpersuasive.
Applicants’ remarks next address the purported evidence that weighs in favor of patentability over Luo.
Therein, it appears that Applicants rely upon the showings in Figures 9 and 10 as being representative of the full scope of cationic lipids ranging from 5 mol% to 40 mol% in combination with the full recited breadth of membrane forming lipids.
Having fully considered the passages from the disclosure and the Figures, the Examiner respectfully submits that while the evidence lends support to the criticality for certain combinations of lipids, it does not lend the same support for the broader recitations of the claims (e.g., claim 1). The Examiner notes further that the combinations and ratios depicted by Figures 9 and 10 are representative of the claims that are already indicated as being free of the prior art.
However, as discussed during the interview, a showing of a specific cationic lipid at 1, 2, or 5% (MVL5) or at 5, 10, or 20% (DDAB) is not considered to be representative of the claimed range of 5-40 mol % as set forth in claim 1. These showings are simply not commensurate in scope with the breadth of the claimed invention.
Applicants next rely on the showings provided in Figures 6 and 11 to demonstrate that stable NLP-polynucleotide complexes are formed, a property that is supposedly neither taught nor suggested by Luo.
At the outset, the Examiner reiterates that the reference teaches and suggests the formation of nanolipoprotein particles having a discoidal lipid bilayer structure and which use a circular apolipoprotein “belt” to help ensure discrete particle sizes and to make the NLPs more thermally stable. See ¶[0003] of Luo.
The discussion of Figure 11 is, like Figures 9 and 10, considered as not being commensurate in scope with the breadth of claim 1. Most notably, the Figure discusses the apparent zeta potential encountered between different ratios of NLP:RNA. However, the only combination of cationic lipid and membrane forming lipid depicted is 2% MVL5 and 98% DMPC, a combination that does not read on any of the instant claims.
Applicants next focus on Figure 6 and the High Throughput analysis performed testing different cationic lipids at various mol% against three different “bulk lipids” (aka membrane forming lipids) with two scaffold proteins (ApoA1 and ApoE). Contrary to the specification, remarks, and Figure, it does not appear that ApoE4 was used in the testing; it cannot be verified.
Applicants assert that Figure 6 supports the conclusion that “concentrations up to 40% (for select lipids like DMTAP, DMEPC, and DODAP in DMPC) yield stable, fully assembled discoidal particles” and that this is in stark contrast to Luo’s indications that any suitable combination of lipids can be used.
Having reviewed the Figure, the Examiner acknowledges that there are select examples of combinations that demonstrate “full cationic-NLP assembly,” as depicted by a rating of “2” or white box. However, the evidence provided, using Applicants’ defined metric (rating of 0-2), is not considered to provide the requisite support for the full scope of the claimed invention. That is, by Applicants’ own definition and admission on the record, the Figure provides a showing of combinations that read on the breadth of the claimed invention, but clearly do not possess the desired result that Applicants appear to correlate to the recited function.
Thus, on its face, Figure 6 instead, supports the Examiner’s position that the evidence is not commensurate in scope with the claimed invention.
Secondly, there is no correlation between the particle ratings (0-2) and the claimed property of being configured to bind a polynucleotide having at least 200 base pairs. The Examiner presumes that a rating of “2” (full cationic-NLP assembly) is the best option and what Applicants consider to provide the claimed function. However, the lesser ratings of “1” and “0” are defined by relative descriptions that do not convey any degree to which binding occurs. Paragraphs [0010], [0110], and [0135] discuss the length of the bindable polynucleotide, and even then do so in an open-ended manner, indicating that the number of base pairs will minimally be 200 bp, all the way up to and in excess of 15,000 bps.
However, it is not discussed what Applicants consider to be the functionality of cationic NLPs having either “marginal loss in yield/homogeneity” or “significant loss in yield/homogeneity”. Further, neither of these ratings appear to be discussed in terms of the ability to bind polynucleotides, and if binding is able to occur, then to what degree (i.e., base pair limitations).
Applicants’ remarks additionally discuss testing assembly of cationic NLPs at different percentages within the range of 5% to 40%. However, the sporadic testing of the cationic lipids is not extended to 40% in all instances, in fact, in only two instances.
The binding data depicted in Figure 9 is discussed as being obtained at defined cationic lipid loadings, and the loadings at or below the low end confirming that 5 mol% is a working boundary at which the binding function emerges.
The description to Figure 9 states that the scaffold protein used was ApoE4 which the Examiner notes as appearing to differ from the generic ApoE scaffold protein used in Figure 6. Secondly, sparingly few of the combinations depicted in Figure 9 correlate to samples prepared and rated in Figure 6. For instance, 5%, 10%, and 20% of MVL5 was combined with DMPC, and each of those used ApoA1 as the scaffold protein. Of those three, only the 20% cationic lipid appeared to provide a full NLP. The combination of DMPC with DDAB (10% and 20%) with ApoE appears to provide a successful outcome.
Thus, having fully considered the cited Figures, the Examiner respectfully disagrees with Applicants’ assessment that the full range of 5mol% to 40mol% of cationic lipid as recited in claim 1 supports the recited function. Figure 6 is considered to specifically affirm the Examiner’s position that criticality for the claimed range is lacking.
Applicants attest that “the property that drives the claimed binding is the net positive surface charge contributed by the cationic lipid,” that “the operative variable is surface charge, and charge scales with cationic content”. The Examiner submits that Luo discusses the use of cationic lipids and that their use influences the charge of the resulting NLPs (see e.g., first sentence of ¶[0057]). From there, ¶[0059] discloses amounts of the different lipids that may be used. Based on the disclosures found in Luo, the Examiner respectfully maintains that it would be well within the understanding of the ordinarily skilled artisan that increasing the amount of lipid of a certain charge (e.g., cationically or positively charged lipid) would similarly increase the presence of that charge within the resulting NLP (i.e., make it more positive).
Responding to Applicants’ “configured to” remarks, the Examiner respectfully maintains, as discussed above, that the phrase itself conveys no additional structural limitations to the claim beyond that which is already recited. Specifically, the claim recites that the cationic lipids are arranged in a discoidal membrane forming a lipid bilayer stabilized by the one or more scaffold proteins. This structural limitation is discussed above as being met by ¶[0003] of the reference.
Having reconsidered the claimed composition with respect to the binding property, the Examiner additionally points out that the claimed NLPs do not exclusively contain cationic lipids. That is, the scope of the claimed invention is such that particles contain 5-40 mol% cationic lipids, thereby being read on by other combinations of lipids having other charges (i.e., negative or neutral).
Applicants’ arguments, for the above reasons, are found unpersuasive. Said rejection is therefore maintained.
New Rejections
Applicants’ amendments have necessitated the following ground(s) of rejection:
Claim Rejections - 35 USC §103
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the Examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicants are 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, 4-8, 11, 16, 17, and 53 are rejected under 35 U.S.C. 103 as being unpatentable over Blanchette et al. (WO 2017/035326 A1; of record).
The limitations of claim 1 are discussed above.
Blanchette discloses a nanolipoprotein particle comprising:
a membrane forming lipid;
a “polymerized” lipid; and
a scaffold protein.
The membrane forming lipid and the polymerized lipid are arranged in a membrane forming lipid bilayer stabilized by the scaffold protein and by the polymerized lipid (see e.g., claim 1).
Regarding the “polymerized” lipid, the Examiner submits that Blanchette provides compositional disclosure whereby the polymerized lipid reads on the instantly claimed “one or more” cationic lipid. [emphasis added] Claims 7 and 22 of the reference provide increasingly narrowed definitions for the “polymerized” lipid, which are considered to teach the instantly claimed cationic lipids of claims 6 and 7.
Claims 9, for instance, discloses the following core formula for the one or more polymerized lipids as being:
PNG
media_image1.png
270
180
media_image1.png
Greyscale
where ‘Y’ is further defined as
PNG
media_image2.png
118
96
media_image2.png
Greyscale
Here, R1, R2, m3, n, o, Y, and R21 all read on the variables as instantly recited by claim 7. The phosphate group (PO4-), m1, and m2, as recited by instant claim 7 need not be present since variables m1, and m2 may each have a value of “0”. Cationic polymers such as DOTAP, DMTAP, and DOTMA are considered to be read on by the foregoing core formula and definitions:
PNG
media_image3.png
75
224
media_image3.png
Greyscale
PNG
media_image4.png
61
234
media_image4.png
Greyscale
Additional lipids that are taught as being used to form membrane forming lipids include: 1,2-dioleoyl-3-trimethyl ammonium-propane (DOTAP), 1,2-di-O-octadecenyl-3-trimethyl-ammonium propane (DOTMA). See ¶[0083].
Claim 2 of the reference discloses that the polymerizable (cationic) lipid is present in a molar concentration of about 5 to about 40 mol%. This reads directly on the limitations of instant claim 1.
Claim 4 of the reference discloses that the total lipid to scaffold protein molar percent ratio ranges from 20:1 to 240:1. This reads directly on the limitations of instant claim 4. The same disclosure is also considered to encompass, and therefore teach the narrower range of 80:1 as recited by claim 5.
Regarding claim 8, the Examiner submits that given the definition of the practiced “total lipid” as defined by claims 1 and 4-6 of Blanchette, that the ratio range of the membrane forming and cationic lipids is met. Therein, the total lipid is composed of the membrane and polymerizable (cationic) lipids. Per claim 5, the membrane forming lipid is present in a range of 60-95 mol% of the total lipid while the polymerizable (cationic) lipid is present in a range of 5-40 mol% of the total lipid. When considered with respect to the 20:1 to 240:1 total lipid to scaffold protein molar percent ratio ranges disclosed by claim 4, the Examiner submits that the limitations of claim 8 are expressly met.
The apolipoprotein limitations of claim 11 are taught by the reference as being a definition for the scaffold protein component. Therein, ¶[0036]-¶[0037] define the term “apolipoprotein” as an amphipathic protein species of scaffold protein which includes: Apolipoproteins A (apo A-I, apo A-II, apo A-IV, and apo A-V), Apolipoproteins B (apo B48 and apo B100), Apolipoproteins C (apo C-I, apo C-II, apo C-III, and apo C-IV), Apolipoproteins D, Apolipoproteins E (e.g., ApoE4), and Apolipoproteins H. See also ¶[0073].
The limitations of claims 16 and 17 are considered to be met by such disclosures as cholesterol and cholesterol modified oligonucleotides. See ¶[0037] and ¶[0115]. In the case of the latter, the cholesterol modified oligonucleotides are taught as being an amphipathic compound that is less lipid like and that a lower mol% (e.g., 0.1-10 mol%) is needed for successful NLP (nanolipoprotein particle) assembly. Such is considered to disclose the recited lower mol% amount of claim 17.
Based on the combined teachings of Blanchette, the Examiner submits that a person of ordinary skill in the art would have had a reasonable expectation of success at producing the instantly claimed nanolipoprotein particles. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, and absent a clear showing of evidence to the contrary.
Based on the combined teachings of the references, the Examiner submits that a person of ordinary skill in the art would have had a reasonable expectation of success at producing the instantly claimed composition and arriving at the recited method of treatment. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, and absent a clear showing of evidence to the contrary.
Allowable Subject Matter
Claims 9, 10, 12-15 and 18 are 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.
Regarding the aforementioned claims, the Examiner’s consideration of the parent application 15/969,311 (allowed as USPN 12,083,223 B2) reveals that the limitations recited therein are each free of the prior art, but remain subject to the rejection of instant claim 1 as discussed above.
All remaining claims are rejected; no claims are allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Jeffrey T. Palenik whose telephone number is (571) 270-1966. The Examiner can normally be reached on 9:30 am - 7:00 pm; M-F (EST).
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 or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Jeffrey T. Palenik/
Primary Examiner, Art Unit 1615
