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 .
DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 2, 2026, that includes a response to the Final Office Action mailed October 30, 2025, has been entered. Claims 30, 33, 34, 37-40, 42, 44, and 45 have been amended; claims 1-29, 41, and 43 have been canceled; and claims 57-59 have been newly added. Claims 37-40 and 44-56 have been withdrawn. Claims 30-36, 42, and 57-59 are under examination in the application.
Claim Objections
Claims 57 and 59 are objected to because of the following:
i) In claim 57, there should be a comma between “(LNP)” and “prepared by rapid mixing”, and also a comma between “microfluidic device” and “comprising”. The expression “using microfluidic device” should be “using a microfluidic device”. There is an improper Markush group. Applicant is advised that a proper Markush group has the general format “selected from the group consisting of A, B, C, and D”, not “selected from the group consisting of A, B, and C, or D”.
ii) In claim 59, the expressions “with positively charged form” and “positively charged form” should be “with the positively charged form” and “the positively charged form”. There should be a comma between “doxycycline” and “or positively charged form of cisplatin”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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 30-36, 42, and 57-59 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 57 stipulates in a wherein clause that the “drug to lipid ratio for doxorubicin is equal to or greater than 0.2”; that the “drug to lipid ratio for doxycycline is equal to or greater than 0.16”, and that the “drug to lipid ratio for cisplatin is equal to or greater than 0.12”. However, the original specification merely discloses that the drug to lipid ratio for LNP encapsulating cisplatin is from about 0.12 to about 0.2; that the drug to lipid ratio for LNP encapsulating doxycycline is from about 0.16 to about 0.45; and that the drug to lipid ratio for LNP encapsulating doxorubicin is from about 0.15 to about 0.55. Hence, while Applicant has adequate support for these ranges, Applicant does not have adequate support for the much broader, open-ended ranges being claimed.
Claim 34 stipulates in a wherein clause that “the weight ratio of the doxorubicin…and the total lipid in the LNP is greater than 0.25”. The original specification provides that the drug to lipid ratio for LNP encapsulating doxorubicin is from about 0.15 to about 0.55, and that this value can specifically be “about 0.25”. Hence, while Applicant has adequate support for the range of about 0.25 to about 0.55, Applicant does not have adequate support for the much broader, open-ended range of “greater than 0.25”.
This constitutes new matter.
Claims 30-36, 42, 58, and 59 depend (ultimately) from claim 57.
Claim Rejections - 35 USC § 112(b)
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 30-36, 42, and 57-59 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 57 is directed to an LNP comprising “an outer lipid monolayer” and “lipid-API complexes”, defines the API as “doxorubicin, doxycycline, cisplatin, or a salt form thereof”, and then recites the “drug to lipid ratio” for each API. One of ordinary skill in the art cannot definitively ascertain what “lipid” must be included in the “drug to lipid ratio”. For example, is the “lipid” in the ratio limited to the anionic lipid in the lipid-API complex? Or, is the “lipid” in the ratio limited to the neutral lipid in the outer lipid monolayer? Or, is the “lipid” in the ratio the combination of all the explicitly disclosed lipids, i.e. the combination of the anionic lipid in the lipid-API complex and the neutral lipid in the outer lipid monolayer? Or, is the “lipid” in the ratio the totality of all the lipids in the LNP, either explicitly mentioned or not? Or what? One of ordinary skill in the art cannot definitively ascertain the metes and bounds of the claimed subject matter.
***For examination at this time, the “drug to lipid ratio” is being interpreted as the drug to lipid ratio in the lipid-API complex.
Claim 59, which depends from claim 57, recites the acronym “EPG” which is not defined by the claim. Claims must stand alone to define the invention, and should not reply on the specification, drawings, or extraneous materials to give them meaning.
Claims 30-36, 42, 58, and 59 are (also) indefinite for depending from an indefinite claim.
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 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. 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.
Claim 30-36, 42, and 57-59 are rejected under 35 U.S.C. 103 as being unpatentable over Jain et al. (Asian J Pharm. 2019; 13(2): 119-124), in view of Wong et al. (J Pharm Sci. 2004; 93(8): 1993-2008), Demant (Eur J Biochem. 1984; 142: 571-575), and Maeki et al. (RSC Adv. 2015; 5: 46181).
Applicant Claims
Applicant’s elected subject matter is directed to a lipid-based nanoparticle (LNP), prepared by rapid mixing using a microfluidic device, comprising an outer lipid monolayer comprising neutral lipids and encapsulating a plurality of anionic lipid-cationic API complexes; wherein the neutral lipid comprises hydrogenated soybean phosphatidylcholine (HSPC), the anionic lipid comprises egg-L-α-phosphatidylglycerol (EPG), and the API is doxorubicin; wherein the LNP further comprises cholesterol; wherein the anionic lipid to neutral lipid molar ratio is 2.5 to 12; wherein the total lipid to cholesterol weight ratio is 10:1 to 1:2; and wherein the weight ratio of doxorubicin to the total lipid in the LNP is equal to or greater than 0.25.
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
Jain et al. disclose a lipid-based nanoparticle (LNP) comprising an outer lipid monolayer comprising hydrogenated soybean phosphatidylcholine (HSPC, i.e. a neutral lipid) encapsulating doxorubicin (i.e. an API) and tristearin; wherein the LNP further comprises cholesterol; and wherein the total lipid to cholesterol weight ratio is about 3:1**.
**Based on 10 mg total lipids consisting of tristearin, HSPC and cholesterol in a weight ratio of 1:1.5:1.2.
Wong et al. disclose a lipid-based nanoparticle (LNP) comprising an outer lipid monolayer encapsulating a plurality of anionic compound-cationic API complexes; wherein the API is doxorubicin and the anionic compound is dextran sulfate (DS); and wherein the doxorubicin to DS weight ratio can be e.g. 5/1.67, which corresponds to a doxorubicin to DS (MW 5000) molar ratio of e.g. about 3.
Demant discloses that Adriamycin (i.e. doxorubicin) forms a complex with negatively-charged phospholipids, including phosphatidylglycerol; wherein the doxorubicin to phosphatidylglycerol molar ratio can be e.g. about 0.6, which corresponds to a doxorubicin to phosphatidylglycerol weight ratio of about 0.44.
Maeki et al. disclose that lipid-based nanoparticles (LNPs) can be advantageously prepared by rapid mixing using a microfluidic device with or without a herringbone mixing element; wherein the technique is relatively simple and easy to use, and produces monodispersed small-sized LNPs which is critical for successfully employing LNPs as a drug carrier in chemotherapy.
Ascertainment of the Difference Between the Scope of the Prior Art and the Claims (MPEP §2141.02)
Jain et al. do not explicitly disclose that the doxorubicin is in a cationic form, that the cationic doxorubicin is in a complex with an anionic lipid, e.g. phosphatidyl-glycerol, and that the LNPs are made by rapid mixing using a microfluidic device. These deficiencies are cured by the teachings of Wong et al., Demant, and Maeki et al.
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been prima facie obvious for one of ordinary skill in the art at the time the present application was filed to combine the respective teachings of Jain et al., Wong et al., Demant, and Maeki et al., outlined supra, to devise Applicant’s presently claimed LNP.
Jain et al. disclose a lipid-based nanoparticle (LNP) comprising an outer lipid monolayer comprising hydrogenated soybean phosphatidylcholine (HSPC, i.e. a neutral lipid) encapsulating doxorubicin (i.e. an API for chemotherapy) and tristearin; wherein the LNP further comprises cholesterol; and wherein the LNP can be employed to deliver doxorubicin for the treatment of brain cancer. Since Wong et al. disclose that complexing cationic doxorubicin with an anionic counterion to thus form an anionic compound-doxorubicin complex enhances loading of doxorubicin into LNP and slows the release rate thus attenuating the possibility of a burst release which can cause undesirable side effects; since Demant discloses that Adriamycin (i.e. doxorubicin) readily forms a complex with negatively-charged phospholipids, including phosphatidylglycerol; and since Maeki et al. disclose that lipid-based nanoparticles (LNPs) can be advantageously prepared by rapid mixing using a microfluidic device with or without a herringbone mixing element; wherein the technique is relatively simple and easy to use, and produces monodispersed small-sized LNPs which is critical for successfully employing LNPs as a drug carrier in chemotherapy; one of ordinary skill in the art would thus be motivated to employ a cationic doxorubicin-anionic phosphatidylglycerol complex in the Jain et al. LNP, and to produce the LNP by rapid mixing using a microfluidic device with or without a herringbone mixing element, with the reasonable expectation that the resulting LNP will be easy to produce, will be monodisperse, and will exhibit enhanced doxorubicin loading and more controlled doxorubicin release, for the successful treatment of brain cancer with reduced side effects.
In view of the cited prior art, one of ordinary skill in the art would thus be motivated to optimize the amount of the anionic lipid, e.g. phosphatidylglycerol, in the LNP system of Jain et al. to achieve the optimal level of doxorubicin loading with the optimal release profile for doxorubicin, and thus one of ordinary skill in the art would thus be able to arrive at an anionic lipid to neutral lipid molar ratio of 2.5-12.
With an anionic lipid to neutral lipid molar ratio of 2.5 to 12, and with the anionic lipid being phosphatidylglycerol and the neutral lipid being HSPC, the weight ratio of anionic lipid to neutral lipid is about 2.5 to 12. Moreover, with a doxorubicin to anionic lipid weight ratio of 0.44, the weight ratio of doxorubicin to the combination of anionic lipid and neutral lipid is about 0.31 to 0.41. Even if the HSPC to cholesterol weight ratio is about 1:1, the weight ratio of doxorubicin to the combination of anionic lipid, neutral lipid, and cholesterol is about 0.24 to 0.38. Hence, one of ordinary skill in the art thus could arrive at an LNP in which the weight ratio of doxorubicin to the total lipid in the LNP is greater than 0.25.
In light of the foregoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed March 2, 2026 have been fully considered but they are not persuasive.
i) Applicant contends that their “invention as claimed in claim 57 provides unexpected result of high drug loading in comparison to that of Wong and Lipodox®” due to Applicant’s “LNP prepared using rapid mixing with anionic lipid complexing with positively charged form of API”; that “a high drug to lipid ratio is recognized in the art as an important property for therapeutic efficacy since a high drug to lipid ratio ensures that adequate amount of the drug is delivered while minimizing other components of the LNP such as lipid/cholesterol that can negatively affect the health of the subject”; and that “Wong shows in FIG. 5A that drug loading %w/w of total particle weight for DOX is about 2% at best” while “in contrast, FIG. 4 of the present specification shows that drug to lipid ratio (D/L) (w/w) for LNP of the present invention comprising doxorubicin is 44% which is 20 times more than Wong’s 2%”.
The Examiner, however, would like to point out the following:
1. First, the present claims simply do not require a doxorubicin to lipid ratio for the LNP of 44%. This is not even a claim limitation that needs to be addressed. Furthermore, the prior art rejection under 35 USC 103 is not over Wong alone. On the contrary, the prior art rejection under 35 USC 103 is over the combination of Jain et al., Wong et al., Demant, and Maeki et al., and what these references expressly disclose and reasonably suggest to one of ordinary skill in the art, who is one of ordinary creativity and not an automaton. Wong is merely a secondary reference cited for disclosing the general principle that complexing cationic doxorubicin with an anionic counterion to thus form an anionic compound-doxorubicin complex enhances loading of doxorubicin into LNP and slows the release rate thus attenuating the possibility of a burst release which can cause undesirable side effects.
2. One of ordinary skill in the art, in view of the cited prior art, would thus arrive at the presently claimed LNP with a reasonable expectation of success, which thus will include complexing cationic doxorubicin with anionic phosphatidylglycerol and producing the LNPs by rapid mixing using a microfluidic device with or without a herringbone mixing element. Applicant admits that their high drug loading is due in large part to their LNP “being prepared using rapid mixing with anionic lipid complexing with positively charged form of API”, both of which are not features disclosed in Wong alone but which would be obvious in view of the cited prior art as a whole.
3. Moreover, Applicant admits that “a high drug to lipid ratio is recognized in the art as an important property for therapeutic efficacy since a high drug to lipid ratio ensures that adequate amount of the drug is delivered while minimizing other components of the LNP such as lipid/cholesterol that can negatively affect the health of the subject”. Indeed, without question, one of ordinary skill in the art would readily know and be motivated to produce a LNP with a high drug to lipid ratio. Obviously, this is done by loading as much doxorubicin into the LNP as possible while employing as little lipid as possible. In view of the cited prior art, one of ordinary skill in the art would be motivated to employ the doxorubicin-anionic lipid complex to facilitate doxorubicin loading and control doxorubicin release, and thus would be motivated to minimize the relative use of the other lipids as far as possible. In other words, Applicant has effectively admitted that one of ordinary skill in the art would be motivated to maximize the anionic lipid to “other lipid” (e.g. neutral lipid, cholesterol) ratio.
4. It turns out that employing rapid mixing using a microfluidic device with or without a herringbone mixing element to manufacture LNPs was not only well known in the art at the time of filing the present application, it was already recognized as a very advantageous method for such purpose. Moreover, it was also known at the time of filing the present application that microfluidic synthesis of LNPs is characterized by complete encapsulation of the active agent over a wide range of conditions (see, e.g. Belliveau et al., Molecular Therapy-Nucleic Acids. 2012; 1: e37). In other words, a high drug loading observed with this microfluidic synthesis technique is not really an unexpected result at all.
For the foregoing reasons, the 35 USC 103 rejection is hereby maintained.
Conclusion
No claims are allowed.
Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID BROWE whose telephone number is (571)270-1320. The examiner can normally be reached Monday - Friday, 9:30 AM to 6 PM EST.
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/DAVID BROWE/Primary Examiner, Art Unit 1617
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