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 .
Applicants’ arguments, filed 03/10/2026, have been fully considered. Rejections and/or objections not reiterated from previous office action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Election/Restrictions
Newly submitted claim 25 is directed to an invention that is independent or distinct from the invention originally claimed for the following reasons:
The invention of the composition (independent claim 1) and newly submitted method (independent claim 25) are related as process of making and product made. The inventions are distinct if either or both of the following can be shown: (1) that the process as claimed can be used to make another and materially different product or (2) that the product as claimed can be made by another and materially different process (MPEP § 806.05(f)). In the instant case, the product can be made by a materially different method, e.g., atomization following by mixing with the tyramine hyaluronic acid.
The methods of using the product (independent claim 21) and the newly submitted method (independent claim 25) are directed to related processes. The related inventions are distinct if: (1) the inventions as claimed are either not capable of use together or can have a materially different design, mode of operation, function, or effect; (2) the inventions do not overlap in scope, i.e., are mutually exclusive; and (3) the inventions as claimed are not obvious variants. See MPEP § 806.05(j). In the instant case, the inventions as claimed are distinct in that they have materially different effects, i.e., treating cancer and making lipid nanoparticles. Furthermore, the inventions as claimed do not encompass overlapping subject matter and there is nothing of record to show them to be obvious variants.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claim 25 withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1 has a degree symbol after the “C” in the last line.
Appropriate correction is required.
Claim Rejections - 35 USC § 112 – New Matter
Claim 1 is 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.
To satisfy the written description requirement, “the missing descriptive matter must necessarily be present in the [original] application’s specification such that one skilled in the art would recognize such a disclosure.” Tronzo v. Biomet, Inc., 156 F.3d 1154, 1159 (Fed. Cir. 1998).
Even if the recitation were obvious over the disclosure of the Specification, that is not the standard for satisfaction of the written description requirement. See In re Huston, 308 F.3d 1267, 1277 (Fed. Cir. 2002) (‘“Entitlement to a filing date does not extend to subject matter which is not disclosed, but would be obvious over what is expressly disclosed.’”).
In the present case the instant specification as originally filed does not support the newly amended limitation in instant claim 1 of “wherein at least a portion of the lipid microparticles is solid at 37° C”. The newly amended limitation limits the melting point of microparticle and appears to allow for individual microparticles with multiple melting points. In contrast, Applicant cites support for a plurality of microparticles wherein individual microparticles have one melting point but necessarily the same melting point (i.e., solid and liquid lipid microparticles; [0078]). While the microparticles may comprise components with different melting points, the microparticles themselves have one melting point (see Table 7 on page 25 & paragraph [0066]).
Therefore, a microparticle having a solid portion is not necessarily present in the disclosure as originally filed and the newly amended claim lacks support.
Claim Rejections - 35 USC § 103 – New by Amendment
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.
1) Claims 1, 3, 5-6, 9-12, 15, 17, 19-21 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Taylor et al (US 2019/0175495 A1, date of publication 06/13/2019; cited in IDS filed 08/02/2023) in view of Sawhney (US 7,413,752 B2, date of patent 08/19/2008).
Regarding instant claim 1 and 17-18, Taylor relates to a hydrogel-based biological delivery vehicle [title] which comprises a hydrogel and drug reservoirs dispersed therein [abstract]. The hydrogel comprises biopolymer backbone containing carboxyl groups, and tyramine may be substituted for at least a portion of the carboxyl groups [abstract]. “More specifically, the composition of the hydrogel matrix may include a glycosaminoglycan such as, but not limited to, sodium hyaluronate (i.e., tyramine cross-linked sodium hyaluronate),” wherein the “tyramine substitution rates [are] from 0.1% to 7.0%” [0057]. Additionally, “preferred embodiments of the binding matrix 102 are comprised of 1.0-5.0% concentration of THA (i.e., 1.0-5.0% THA in water)” [0045]. Taylor teaches system allows for localized delivery; “a chemo toxic agent could be supplied from the mass in locally relatively high concentration that would impact fast growing cells nearby (i.e. tumors), but that will not impact the entire biological system in the same way” [0039]. Finally, Taylor does disclose the drug reservoir particles “come in a variety of sizes (for example, submicron to macro particles)” [0064] and include liposomes [0026].
Taylor does not disclose lipid microparticles that are not liposomes.
Sawhney discloses compositions which “control the release of relatively low molecular weight therapeutic species through hydrogels by first dispersing or dissolving such therapeutic species within relatively hydrophobic rate modifying agents to form a mixture” [abstract]. In one embodiment “[t]he hydrophobic oil phase may be formed by one of several methods, including spray-forming and oil-based hot melt microencapsulation. In the spray-forming method, a low melting temperature release rate modifying agent is used and a known amount of the active drug is suspended (for insoluble drugs) or co-dissolved (for soluble drugs) by a melt mixing step. The solution or dispersion is then sprayed into a cooled stream of air, a bath of cold water, or a hydrogel precursor solution. Microparticles ranging in size between 1-10 microns are obtained, having a morphology that depends on the type of release rate modifying agent used and its melt viscosity” [col. 12, lines 45-56]. Examples of specific release modifying agents include stearic acid with a melting point of 71.2 deg. C (i.e., instant claims 6, 9) [col. 14, Table 1]. Therapeutic agents include antitumor agents [col. 10, line 3]. Finally, Sawhney teaches that liposomes are not ideal candidates for the “hydrophobic rate modifying agents” because they “are quickly cleared from the blood by uptake through the reticuloendothelial system” [col. 5, lines 28-29].
It would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have simply substituted the hydrophobic rate modifying agents (i.e., microparticle drug reservoirs) of Sawhney in place of the drug reservoirs disclosed by Taylor. One would have been motivated to make this substitution because Sawhney discloses liposomes are quickly cleared from the blood by uptake through the reticuloendothelial system. One would have had a reasonable expectation of success because, like the drug reservoirs of Taylor, the drug reservoirs of Sawhney are intended be dispersed in a hydrogel in order to control the release of the drug into the hydrogel matrix. The simple substitution of one known element (e.g., the microparticles of Sawhney) in place of another (e.g., the drug reservoirs of Taylor) in order to achieve predictable results (controlled released drug reservoir) is prima facie obvious. See MPEP 2143, Exemplary Rationale B.
Additionally, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). In the present case the claimed ranges for particle size (instant claims 19 and 20) lie inside the range of the prior art and a prima facie case of obviousness exists. Also, the claimed degree of tyramine substitution (0.5-3%) and concentration of tyramine substituted hyaluronic acid (0.1%-1%) overlap with the ranges discloses in the prior art (0.1%-7% and 1%-5%, respectively) and so a prima facie case of obviousness exists for each.
Therefore, it would have been obvious to one of ordinary skill in the art, at the time of filling, to have formulated to have formulated a composition comprising lipid microparticles dispersed in a hyaluronic hydrogel, wherein 0.5-3% of the hydroxyl groups are substituted for tyramine and wherein the lipid microparticles comprise an antitumor agent. Wherein the tyramine substituted hyaluronic acid is present within the instantly claimed amounts. Wherein at least a portion of the lipid microparticle is solid at 37 deg. C (stearic acid).
Regarding instant claim 3, Taylor discloses the delivery system may “incorporate chemotoxic compounds, monoclonal antibodies targeting tumor specific antigens” [0192] and that a “chemotoxic agent may be added to the binding matrix 102 and/or drug reservoirs 104 that can elute into the surrounding tissues 108a and provide a locally high concentration of the chemotoxic compound” [0193].
It would have been obvious to one of ordinary skill in the art, at the time of filling, to have simply substituted the chemotoxic agent in the binding matrix for the monoclonal antibodies (i.e., biologic antitumor agent) because Taylor discloses the system may comprise either. One would have been motivated make this substitution to provide a monoclonal antibodies targeting tumor specific antigens at locally high concentrations. One would have had an expectation of success because Taylor discloses the delivery system may comprise a chemotoxic compound and a monoclonal antibodies targeting tumor specific antigens. See MPEP 2143, Exemplary Rationale B.
Therefore, it would have been obvious to one of ordinary skill in the art, at the time of filling, to formulated the composition taught by Taylor and Sawhney to comprise a biologic antitumor agent dissolved in the aqueous carrier (i.e., the hydrogel).
In regard to claim 5, the instantly claimed volumetric ratio would have also been obvious because “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation" (see MPEP 2144.05 IIA quoting In re Aller, 220 F.2d 454, 456 (105 USPQ 233)). In the present case the claimed lipid and aqueous phases are disclosed by the prior art and so the ratio of one to the other would have been obvious through routine experimentation. It is within the purview of the artisan to determine result effective amounts of the ingredients beneficially taught by the prior art.
Regarding instant claims 10-12, Sawhney discloses “hydrophobic materials which may be suitable for use as release rate modifying agents in the carrier system are selected from the group consisting of long chain carboxylic acids, long chain carboxylic acid esters, long chain carboxylic acid alcohols and mixtures thereof” [col. 15, lines 57-61]. Sawney discloses that long chain carboxylic acids contain 6-30 carbons [col. 15, line 63] and include lauric acid, myristic acid, palmitic acid stearic acid and oleic acid [col. 16 lines 4-5 & 7].
It would have been obvious to one of ordinary skill in the art, at the time of filling, to have formulated a composition comprising stearic acid, oleic acid, myristic acid, palmitic acid and lauric acid within the instantly claimed amounts through routine optimization. It has been held that it is not inventive to discover the optimum workable ranges by routine experimentation where, as is here, the general conditions of the claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). One of ordinary skill in the art would have been motivated to optimize the composition disclosed by Sawhney because the “normal desire of scientists to improve upon what is already generally known”. Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382. Please refer to MPEP 2144.05. One would have had an expectation of success because Sawhney discloses mixtures of fatty acids may be used for the lipid particle.
Therefore, it would have been obvious to one of ordinary skill in the art, at the time of filling, to formulated the drug delivery system taught by Taylor to comprise lipid particles comprising stearic acid, oleic acid, myristic acid, palmitic acid and lauric acid at the claimed amounts.
Regarding instant claim 15, Sawhney discloses “[t]he release rate modifying agents may be solids or liquids at room temperature” [col. 14, lines 17-18]. Examples of specific release modifying agents include capric acid with a melting point of 31.4 deg. C and stearic acid with a melting point of 71.2 deg. C [col. 14, Table 1].
Generally, it is prima facie obvious to select a known material based on its suitability for its intended use. See MPEP 2144.07.
It would have been obvious to one of ordinary skill in the art, at the time of filling, to have selected capric acid microparticles and stearic acid microparticles of Sawhney as the drug reservoirs, because Sawhney discloses each (i.e., a liquid microparticle and a solid microparticle) is suitable to be dispersed in a hydrogel and to encapsulate a therapeutic agent.
Therefore, it would have been obvious to one of ordinary skill in the art, at the time of filling, to have formulated the composition taught by Taylor and Sawhney as discussed above, wherein the drug reservoir microparticles comprise lipid microparticles that are solid at 37 deg C and lipid microparticles that are liquid at 37 deg C.
Regarding instant claim 17, Sawhney discloses the antitumor agent may be daunorubicin hydrochloride (i.e., anthracycline) [col. 11, line 29].
Regarding the independent claim 21, Taylor discloses the delivery system may can be “injected within or near the target tumor” [0053].
Taylor does not anticipate the method of independent claim 21 because it does not disclose all the elements in one example or embodiment.
However, given the disclosure of each component individually, it would have been prima facie obvious for a person having ordinary skill in the art at, at the time of filling, to have selected and combined known components for their established functions with predictable results by following the teachings of Taylor. MPEP 2143 and 2144.06(I).
Therefore, it would have been obvious to one of ordinary skill in the art, at the time of filling, to have administered the composition taught by Taylor and Sawhney, and discussed above (i.e., a hydrogel binding matrix, a plurality of lipid microparticles and an antitumor agent), to a tumor.
In regard to claim 24, it is noted that the claim scope is not limited by claim language, i.e. "wherein" or "whereby" clauses, that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure (see MPEP 2111.04). The court in Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005) noted (quoting Minton v. Nat'l Ass'n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a "'whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited'"(see Id.) In the present case the prior art teaches all the instantly claimed method steps, as well as compositions comprising substantially the same components, in the same relative amounts, and so it would have been expected to have the elution rate of the prior art.
2) Claims 2, 3, 4 are rejected under 35 U.S.C. 103 as being unpatentable over Taylor et al (US 2019/0175495 A1, date of publication 06/13/2019; cited in IDS filed 08/02/2023) in view of Sawhney (US 7,413,752 B2, date of patent 08/19/2008) as applied to claims 1, 3, 5-6, 9-12, 15, 17, 19-21 and 24 above, and in further view of Goldberg et al. (WO 2018/045058, publication date 03/08/2018; cited in IDS filed 08/02/2023).
Taylor and Sawhney, which are taught above, differ from the instant claims insofar as they do not teach a salt of an antitumor agent dissolved in the aqueous carrier and bevacizumab. However, Taylor does disclose “chemotoxic agent may be added to the binding matrix” [0193] and that the drug delivery system may “incorporate chemotoxic compounds, [and] monoclonal antibodies targeting tumor specific antigens” [0192].
Goldberg relates to a drug delivery device for treating cancer and metastatic tumors and discloses “drug delivery device is provided that comprises a biodegradable scaffold carrying one or more anti-cancer therapeutic agents” [abstract]. Additionally, “[i]n certain embodiments, the biomaterial is a hydrogel. Hydrogels can provide a scaffold that allows the components of the composition or device to be combined effectively and form a drug delivery system that is implantable in a surgical setting. In certain embodiments, the hydrogel is prepared from hyaluronic acid” (p. 3, [00012]). According to Goldberg the chemotherapeutic can be an anthracycline such as daunorubicin or pharmaceutically acceptable salts thereof (see the last 7 lines of [000270] on page 66; instant claims 2). Goldberg also discloses that “[i]n certain embodiments, the drug delivery compositions and devices may further comprise a targeted agent” (p. 66, [000272]), such as bevacizumab (see line 8, [000273], p. 67; instant claims 3-4)
Generally, it is prima facie obvious to select a known material based on its suitability for its intended use. See MPEP 2144.07.
It would have been obvious to one of ordinary skill in the art, at the time of filling, to have selected a pharmaceutically acceptable salt of daunorubicin and bevacizumab as the chemotoxic agent and the targeting agent in the binding matrix (i.e., hydrogel) desired by Taylor, because Goldberg discloses they are suitable materials for that purpose.
Therefore, it would have been obvious to one of ordinary skill in the art, at the time of filling, to have formulated to the drug delivery system taught by Taylor and Sawhney to comprise a salt of the antitumor agent (daunorubicin) or bevacizumab in the aqueous phase (i.e., hydrogel).
3) Claims 7 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Taylor et al (US 2019/0175495 A1, date of publication 06/13/2019; cited in IDS filed 08/02/2023) in view of Sawhney (US 7,413,752 B2, date of patent 08/19/2008) as applied to instant claims 1, 3, 5-6, 9-12, 15, 17, 19-21 and 24, and in further Liu et al. (CN 103976950 A, publication date 08/13/2014; citing machine English translation).
Taylor and Sawhney, which are taught above, differ from the instant claims insofar as they do not teach the instantly claimed amounts of fatty acids. Sawhney does, however, disclose the “[u]seful release rate modifying agents include, for example, fatty acids, triglycerides, and other like hydrophobic compounds, and may include, for example, … cholesterol” [col. 15, lines 16-18 & 29]. Sawhney also discloses oleic acid [col. 16, line 7]. Therapeutic agents include antitumor agents [col. 10, line 3] and may be hydrophobic [col. 16, line 51].
Liu relates to a drug delivery system and “discloses a doxorubicin nano drug loading system, its preparation method and application. The drug-loading system comprises 0.02%-1.5% of active ingredients containing doxorubicin, 1-20% of solid lipids, 0.1-20% of liquid lipids, 0.5%-20% of emulsifiers and isotonic regulators according to the mass ratio. 0.1%-5%; solid lipids and liquid lipids form nanoparticles to encapsulate the active ingredient containing doxorubicin … The doxorubicin nano-loading system realizes co-delivery of doxorubicin and chemotherapy sensitizer, and enhances the lethality of doxorubicin to liver cancer cells” [abstract]. Liu disclose the solid lipid may be cholesterol and the liquid lipid may be oleic acid (i.e., instant claims 6 and 9 [p. 10, last two paragraphs]. Therefore, Liu teaches a particle comprising 0.02%-1.5% of active ingredients containing doxorubicin, 1-20% cholesterol (i.e., not fatty acid) as the solid lipid, 0.1-20% of oleic acid as the liquid lipids, 0.5%-20% of emulsifiers and isotonic regulators.
Generally, it is prima facie obvious to select a known material based on its suitability for its intended use. See MPEP 2144.07.
In the present case, it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have selected the mixture fo cholesterol and oleic acid disclosed by Liu for the drug reservoirs of Sawhney because Liu discloses it is an appropriate makeup for lipid drug reservoirs loaded with an antitumor agent. A skilled artisan would have had an expectation of success because Sawhney discloses cholesterol and oleic acid are both useful for making the rate modifying microparticles.
Similarly it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have selected the doxorubicin of Liu for the antitumor agent desired by Sawhney, because Liu discloses it is a suitable antitumor agent to load into lipid drug reservoirs. One would have had an expectation of success because discloses the therapeutic agents may be hydrophobic.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). In the present case the instantly claimed range of fatty acids in the microparticle (less than 50%) overlaps with the range of the prior art (e.g., 20% cholesterol and 0.1% oleic acid), and so a prima facie case of obviousness exists.
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have formulated the composition taught by Taylor and Sawhney such that the lipid microparticles (drug reservoirs) comprised a fatty acid in amounts less than 50% w/w and doxorubicin.
4) Claims 22 and 23 is rejected under 35 U.S.C. 103 as being unpatentable over Taylor et al (US 2019/0175495 A1, date of publication 06/13/2019; cited in IDS filed 08/02/2023) in view of Sawhney (US 7,413,752 B2, date of patent 08/19/2008) as applied to claims 1, 3, 5-6, 9-12, 15, 17, 19-21 and 24 above, and in further view of Kortuc (WO 2021256427 A1, publication date 12/23/2021; citing English machine translation).
Taylor and Sawhney, which are taught above, differ from the instant claims insofar as they do not disclose administering the composition with a guided needle and ultrasound imagine.
Kortuc discloses that by “injecting a specific amount of a cancer-treatment sensitiser, which is produced by combining H2O2 in a specified concentration range with hyaluronic acid, into a tumour-effected area in a specific procedure, it is possible to increase the effectiveness of cancer treatments such as radiotherapy or anti-cancer chemotherapy” [abstract]. Kortuc discloses the hyaluronic acid may be in the form of a hydrogel [p. 10, penultimate paragraph]. Kortuc discloses that “[i]njections were made with a 23 gauge needle by a trained radiologist or radiologist under ultrasound (US) guidance” [p. 24, last paragraph] and that “[w]ith the rapid appearance of oxygen microbubbles (see Figure 3C) as H2O2 decomposes into oxygen and water in the tumor, it is uniform under US [ultrasound] guidance through 2 to 3 different angle needle marks” [p. 25, para. 1]. “The number of needle marks in the tumor and the point of entry into the skin were determined by the radiologist during the ultrasound scan and were guided by the extent and distribution of oxygen microbubbles during the injection procedure” [p. 25, para. 2].
It would have been obvious to one of ordinary skill in the art, at the time of filling, to have modified the method of administering disclosed by Taylor to include the guided needle delivery and verification via ultrasound disclosed by Kortuc. One would have been motivated to combined these methods for the improved effectiveness disclosed by Kortuc. One would have had an expectation of success because Kortuc discloses it can improve effectiveness of chemotherapeutics and discloses a composition comprising hyaluronic acid. See MPEP 2143, Exemplary Rationale A.
Therefore, it would have been obvious to one of ordinary skill in the art, at the time of filling, to have administered the composition taught by Taylor and Sawhney, and discussed above (i.e., a hydrogel binding matrix, a plurality of lipid microparticles and an antitumor agent), to a tumor, which is to say, to treat cancer in a subject in need thereof. Wherein the composition is administered by guided needle and targeting is confirmed via ultrasound imaging.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
1) Claims 1-7, 9-12, 15, and 17-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 17/965,738 in view of Taylor et al (US 2019/0175495 A1, date of publication 06/13/2019; cited in IDS filed 08/02/2023), Goldberg et al. (WO 2018/045058, publication date 03/08/2018; cited in IDS filed 08/02/2023) and Liu et al. (CN 103976950 A, publication date 08/13/2014; citing machine English translation).
Both the instant claims and the copending claims disclose a composition comprising: an aqueous carrier; and a plurality of lipid microparticles comprising an active agent dispersed within the aqueous carrier, wherein the aqueous carrier is hydrogel comprised of tyramine substituted hyaluronic acid, wherein the hydrogel is formed through di-tyramine crosslinking and wherein the degree of tyramine substitution of hyaluronic acid hydroxyl groups is about 0.5% to about 3% [claims 1 and 2; instant claim 1]. Furthermore, both the instant claims and the copending claims disclose the microparticle comprises lauric acid (i.e., fatty acid with even number of carbons and melting point greater than 37 deg. C1) [claim 4; instant claims 6 and 9] and a microparticle comprising less than 50% fatty acid [claims 7 and 8; instant claim 7]. Both the instant claims and the copending claims also disclose a method of administering comprising echogenic targeting and confirming delivery via ultrasound [claim 1; instant claims 21 and 23]. The copending claims and the instant claims also both teach liquid and solid microparticles: “wherein the lipid phase is a triglyceride” [claim 11] “wherein the triglyceride is a liquid at 25°C” and “wherein the plurality of lipid microparticles are comprised of a lauric acid” [claim 4] (i.e., instant claim 15).
The claims differ insofar as the copending claims disclose the active agent is an anesthetic agent, not an antitumor agent.
Taylor relates to a hydrogel-based biological delivery vehicle [title] which comprises a hydrogel and drug reservoirs dispersed therein [abstract]. Wherein the hydrogel is tyramine cross-linked sodium hyaluronate [0057]. Taylor also discloses that “loading the drug reservoirs 104 with endotoxins/pyrogens or cytokines can elicit a locally large immune response, which may activate the patient's immune system to recognize a cancer near the placed delivery system 100 as foreign and attack the tumor cells” (i.e., drug reservoir loaded with an immune stimulating antitumor agent; instant claim 17) [0040]. Additionally, Taylor discloses that in “preferred embodiments of the binding matrix 102 are comprised of 1.0-5.0% concentration of THA (i.e., 1.0-5.0% THA in water)” [0045].
It would have been obvious to one of ordinary skill in the art, at the time of filling, to have to have simply substituted the anesthetic agent of the copending claims for the antitumor active disclosed by Taylor and to have administered the composition to treat cancer, because Taylor discloses similar hydrogel systems may be used to deliver antitumor agents. See MPEP 2143, Exemplary Rationale B.
It also would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have selected the THA concentration range of Taylor for the concentration in the composition taught by the copending claims because Taylor discloses it is suitable for a THA based hydrogel delivery system. See MPEP 2144.07.
The copending claims disclose “the volumetric ratio between the aqueous carrier and the lipid microparticles is from about 60-90 the aqueous carrier to about 40-10 lipid microparticles” and so a prima facie case of obviousness exists for instant claim 5. See MPEP 2144.05(I).
Regarding instant claim 3, Taylor discloses the delivery system may “incorporate chemotoxic compounds, monoclonal antibodies targeting tumor specific antigens” (i.e., biologic antitumor agent) [0192] and that a “chemotoxic agent may be added to the binding matrix 102 and/or drug reservoirs 104 that can elute into the surrounding tissues 108a and provide a locally high concentration of the chemotoxic compound” [0193]. It would have been obvious to one of ordinary skill in the art, at the time of filling, to have combined the teachings of Taylor that the matrix may comprise a chemotoxic agent and that the delivery system may also comprise biologic antitumor agent with the delivery system of the copending claims because the two delivery systems are so similar. One would have been motivated to do so to provide an delivery system with antitumor activity. See MPEP 2143, Exemplary Rationale A.
Goldberg discloses a drug delivery system comprising a hyaluronic hydrogel scaffold carrying anti-cancer agents [abstract & (p. 3, [00012])]. Goldberg discloses the agents may be doxorubicin or pharmaceutically acceptable salts thereof (see the last 7 lines of [000270] on page 66) and bevacizumab (see line 8, [000273]).
It would have been obvious to one of ordinary skill in the art, at the time of filling, to have to have selected these agents for the anti-cancer agents desired by Taylor because Goldberg discloses they are suitable for hydrogel delivery systems. See MPEP 2144.07.
The copending claims teach a delivery system with lipid phase droplets from about 500nm to about 5 micrometers [claim 12].
Liu relates to a drug delivery system and “discloses a doxorubicin nano drug loading system, its preparation method and application. The drug-loading system comprises 0.02%-1.5% of active ingredients containing doxorubicin, 1-20% of solid lipids, 0.1-20% of liquid lipids, 0.5%-20% of emulsifiers and isotonic regulators according to the mass ratio. 0.1%-5%; solid lipids and liquid lipids form nanoparticles to encapsulate the active ingredient containing doxorubicin … The doxorubicin nano-loading system realizes co-delivery of doxorubicin and chemotherapy sensitizer, and enhances the lethality of doxorubicin to liver cancer cells” [abstract]. “[T]he nanometer drug delivery system has a particle size of nanoparticles between 10nm and 1000nm” [p. 5, para. 3].
Generally, it is prima facie obvious to select a known material based on its suitability for its intended use. See MPEP 2144.07.
It would have been obvious to one of ordinary skill in the art, at the time of filling, to have to have used the lipid makeup Liu for the lipid particles discloses by the copending claims because Liu discloses it is a suitable composition for drug loaded lipid particles.
Additionally, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). In the present case the claim ranges for the particle size (5 microns or less and 5-20 microns; instant claims 20 and 19, respectively) overlap with prior art range for particle size (i.e., 500nm to 5 microns) and so a prima facie case of obviousness exists.
Regarding instant claims 10-12, Liu discloses the solid lipid may also be a saturated fatty acid such as lauric acid, myristic acid palmitic acid and stearic acid [p. 10, penultimate paragraph] and the liquid lipid may be oleic acid [p. 10, last paragraph].
It would have been obvious to one of ordinary skill in the art, at the time of filling, to have formulated a composition comprising stearic acid, oleic acid, myristic acid, palmitic acid and lauric acid within the instantly claimed amounts through routine optimization. It has been held that it is not inventive to discover the optimum workable ranges by routine experimentation where, as is here, the general conditions of the claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). One of ordinary skill in the art would have been motivated to optimize the composition disclosed by Liu because the “normal desire of scientists to improve upon what is already generally known”. Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382. Please refer to MPEP 2144.05. One would have had an expectation of success because Liu discloses mixtures of fatty acids may be used for the lipid particle.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
1) On page 9 of their Remarks, Applicant argues that “Taylor does not disclose a range of 0.5-3% THA tyramine substitution at all, nor does Taylor disclose a hydrogel that has about 0.1 % to about 1 % THA”.
This argument is not persuasive. As discussed above, Taylor discloses overlapping ranges and so a prima facie case of obviousness exists. See MPEP 2144.05 II.
2) On pages 9 and 10 of their Remarks, Applicant argues that Taylor does not disclose lipid nanoparticles that are not liposomes. Applicant further asserts that a skilled artisan would not have understood how to combine the lipid microparticles of Liu with the tyramine substituted hyaluronic acid hydrogel aqueous phase of Taylor because: “Liu does not disclose any hydrogel at all”, the references do not provide guidance on making the substitution and a skilled artisan would not have considered the lipid nanoparticles of Liu separable from the emulsion.
This argument is moot in view of the new grounds of rejections necessitated by amendment.
3) On pages 10-11 of their Remarks, Applicant argues that combining the particles of Lui with the carrier of Taylor would have changed the principal of operation of Taylor as the primary reference. Applicant asserts that “Liu changes the principle of operation, since it would not be expected that a lipid soluble active ingredient would elute from a lipid-based nanoparticle into a water-based hydrogel in Taylor due to differences in solubility.”
This argument is moot in view of the new grounds of rejections necessitated by amendment.
4) On page 11 of their Remarks, Applicant argues that modifying Liu with Taylor would have changed the principle of operation of Liu.
This argument is moot because Liu is not the primary reference.
5) On page 11 of their Remarks, Applicant argues that any combination of Goldberg, Sawhney and/or Kortuc do not remedy the deficiencies of Taylor and Liu because no references disclose hydrogel containing about 0.1-1 % THA with 0.5-3% THA substitution rate, either as individual features or combined.
The Examiner disagrees. As discussed above Taylor discloses a hydrogel with overlapping ranges. For example see paragraph 43 of Taylor: “More specifically, preferred embodiments of the binding matrix 102 are comprised of 1.0-5.0% concentration of THA (i.e., 1.0-5.0% THA in water) with tyramine substitutions at or
below 1.5%.” Therefore, the instantly claimed ranges are prima facie obvious because in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
6) On page 12 of their Remarks, Applicant argues that the double patenting rejection should be withdrawn because the copending application 17/965,738 does not disclose “1. THA concentration of 0.1-1 %, 2. lipid phase comprising antitumor agent
or any antitumor agent at all, and 3. lipid microparticles that are solid at 37° C (lipid phase droplets are liquid at 25° C).”
This argument is not persuasive. As discussed above, Taylor teaches a THA based hydrogel delivery systems and teaches THA concentrations which overlap with the instantly claimed ranges an antitumor active agents (see Taylor at [abstract], [0057], [0040], [0045]). Taylor remedies the first and second deficiencies in the copending claims identified by Applicant. The copending claims disclose lauric acid which is solid at 37 deg. C, as evidenced by PubChem Compound Summary for CID 3893, Lauric Acid. Therefore, the copending claims do, in fact, disclose a lipid particles that a solid at 37 deg. C. The instant claims do not disclose lipid phase droplets are liquid at 25° C.
Technological Background
The prior art made of record is considered pertinent to applicant's disclosure.
PubChem Compound Summary for CID 3893, Lauric Acid. Retrieved April 16, 2026 from https://pubchem.ncbi.nlm.nih.gov/compound/Lauric-Acid, which is pertinent for teaching the melting point of lauric acid at page 15.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/C.T.W./Examiner, Art Unit 1612
/WALTER E WEBB/Primary Examiner, Art Unit 1612
1 PubChem Compound Summary for CID 3893, Lauric Acid. Retrieved April 16, 2026 from https://pubchem.ncbi.nlm.nih.gov/compound/Lauric-Acid.
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