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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 December 29, 2025 has been entered.
Applicants' arguments, filed December 29, 2025, have been fully considered but they are not deemed to be fully persuasive. The following rejections and/or objections constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 112 – New Matter
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 24 – 30, 39 and 40 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. This is a new matter rejection.
Claim 24, from which all other claims depend, has been amended to recite that “the stereocomplex is loaded inside a core of the micelles and is associated with oligolactic acid in the core of the micelle” and this limitation is not supported by the disclosure as originally filed. The stereocomplex contains oligolactic and is therefore not associated in any possible way but in a particular alignment based on the complementary stereochemistry of the L- and D- oligolactic acid materials. This claim language is either requiring an additional oligolactic acid in the core beyond that which is present in the stereocomplex and/or broadening the scope of the possible arrangements of the oligolactic acid fragments in the stereocomplexes. None of the cited sections support for such structures.
The dependent claims fall therewith.
If Applicant is in disagreement with the Examiner regarding support for the amended claim, Applicant is respectfully requested to point to additional locations wherein support may be found for the instant invention as the provided citations do not provide sufficient support.
Claim 40 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. This is a new matter rejection.
Claim 40 requires not only a cylindrical morphology for the micelles but also that the length is in the range of about 140 nm to about 200 nm and this size range for the length of the particles is not supported by the disclosure as originally filed. The only place such size values are disclosed in the specification as originally filed is ¶ [0074] of the PGPub of the instant application. Micelles with 5.4% and 15.3% o(L+DLA)10-GEM in PEG-b-PLA micelles showed hydrodynamic diameters of about 140 nm and about 200 nm respectively. Hydrodynamic size measurements do not necessarily say much about the actual diameter of the particles (see “What’s a More Useful Measurement – A Particle’s Hydrodynamic Diameter or its ‘Core’ Diameter?” from nanoparticleanalyzer.com). Based on ¶ [0059] of the PGPub of the instant application, it appears that particle size was determined using dynamic light scattering (DLS). As discussed by “Sizing Particles” webpage from americanlaboratory.com (accessed March 10, 2026), light scattering measurements assume spherical particles (p 2, last paragraph) and therefore diameters from such methods do not necessarily appear applicable to non-spherical shapes such as cylinders. Therefore the reported hydrodynamic diameter of particles, that could be calculated based on the assumption of spherical particles, does not provide support for the full scope of lengths for the cylindrical micelles recited in claim 40 which permit any amount of the stereocomplex and made with all possible number of lactic acid subunits for cylinders with a length falling within the claimed range and length, whether absolute or hydrodynamic, for the cylindrical micelles.
If Applicant is in disagreement with the Examiner regarding support for the amended claim, Applicant is respectfully requested to point to additional locations wherein support may be found for the instant invention as the provided citations do not provide sufficient support and/or explain how the values in the disclosure as originally filed are sufficient to support the full scope of claim 40.
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 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(s) 24 – 30, 39 and 40 were rejected under 35 U.S.C. 103 as being unpatentable over Kruse et al. (Pharazie, 2013) in view of Bertin (Macromol Chem Phy, 2012) and Daman et al. (Int J Pharm, 2014) further in view of Tam et al. (JACS, 2016) and Chen et al. (J Nanoparticle Res, 2007). This rejection is MAINTAINED for the reasons of record set forth herein.
Kruse et al. discloses prodrugs are a straightforward way to ‘individualize’ drug properties and generally are designed to change the HLB (hydrophilic-lipophilic balance) of a drug, improve resorption and cellular uptake, modulate organ specificity, achieve retarded drug action, increase plasma stability, modify metabolism or reduced toxicity (p 93, col 1). PEG (polyethylene glycol) is a frequently applied to prodrug modification and the conformation of the PEG polymer is largely defined by a stereochemical gauche effect, resulting in the chain adopting a stretched helical confirmation in aqueous solutions, reaching out into the surrounding space like antenna, providing a perfect conformation for hydratisation with relatively low interactions with the drug (p 93, col 1). Polylactic acid (PLA) is physiologically well accepted, biodegradable and broadly used as carrier [sic] for pharmaceutical active ingredients in drug delivery systems (p 93, col 1). Like PEGs, oligomers of lactic acid (OLAs) exhibition conformation properties defined by stereochemical effects and are promising candidates for non-toxic prodrug moieties (p 93, col 2, ¶ 1). OLAs prefer a helical confirmation as shown in figure 1 that is similar to that of PEG chains. As shown on p 94, two different schemes were used to prepared OLAs of different lengths and stereochemistry (section 2.1), and coupled to ibuprofen to prepare a prodrug (section 2.4), with ibuprofen being selected as a model drug (p 93, col 2, ¶ 2). Favorable properties for prodrugs such as high stability towards non selective esterases (the ibuprofen was attached via an ester linkage) and plasma stability demonstrate that OLA-moieties are promising candidates for use as prodrugs (section 2.7).
The formation of a stereocomplex (SC) comprising lactic acid oligomers of complementary stereochemistry is not disclosed.
Bertin discloses that for biomedical of applications of polymers such as drug delivery systems, fine tuning of the drug delivery rate and strength of the material is needed along with biocompatibility and biodegradability (p 2329, cols 1 and 2). Polymers or complexes thereof that fulfill the biocompatibility criteria offer the possibility to finely tune the thermal and mechanical performances, and (bio)degradation rate according to a given application are highly valuable, with stereocomplex of polymers being of great interest (p 2329, col 3). SCs shows improved thermal and mechanical resistance, as well as a slower degradation rate compared to the individual homopolymers due to their higher crystallinity (p 2330, col 1, ¶ 1). Homostereocomplexes are formed from complementary polymers with the same chemical compositions and can be two opposite enantiomeric polymers such as the L- and D-enantiomers of PLA (polylactic acid; p 2330, col 1, ¶ 1). PLA is derived from renewable resources, has good biocompatibility in vivo, is biodegradable under physiological conditions and is approved by the U.S. Food and Drug Administration for various biomedical applications (p 2330, col 1, ¶ 2). SCs of PLA can be obtained by co-crystallization of a 1:1 mixture of enantiomeric PLLA and PDLA, which can take place in bulk or solution conditions (¶ bridging cols 2 and 3 on p 2330). The lactate length needed for SC formation is 7 lactate repeat units, which is shorter than the 11 lactate repeat units needed for homocrystallization (p 2330, col 3; note that the lactate unit or lactic acid unit is half of the lactide unit). The melting point of the PLA SC is about 50°C higher than the melting point of the component homopolymers with solutions of the SC PLA having increased viscosity and shear storage modulus G’ (p 2331, col 1, ¶ 1). Section 2.1 describes the use of these materials in therapeutic and drug delivery systems, although description of the entire drug release process is difficult due to the number of processes involved and the various physicochemical characteristics of the drug and DDS (drug delivery system; section 2.1) and include structures such as nanoparticles or micelles that require the presence of amphiphilic material such as the linear PEG-PLA referenced at the bottom of col 2 on p 2333. Benefits of SCs include a more compact crystal structure and improved mechanical strength, with PLA SCs showing a greater stability for nanoparticles (NPs), slower degradation for microspheres, stronger hydrogels with faster gelation and a slower erosion profile (p 2351, col 1, ¶ 2). SCs might also be a synthetic alternative to triblock copolymers or even more complex macromolecular architectures with great potential for the fine tuning of nanostructures (p 2351, col 2).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to prepare prodrug conjugates as in Kruse et al. using PLA oligomers of complementary stereochemistries and then contacting those oligomers with each other to form PLA SCs, which requires at least 7 repeat units in the oligolactic acid moiety to form. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Kruse discloses that the addition of oligolactic acid moieties can form prodrugs to among other features, change the HLB balance of the drug. Bertin discloses that the improved properties of lactic acid containing materials arising from SC formation, such as those prepared from a 1:1 mixture of the D- and L-enantiomers of lactic acid. At least 7 such units are required for SC complex formation so the person of ordinary skill would use oligomers of at least such a length to prepare a stereocomplex of the oligolactic acid prodrugs as in Kruse. The overall length of oligo- or poly-lactic acid is also important for the properties of the material such as the degradation rate. There is no evidence of record as to the criticality of the claimed oligomer length which overlaps with the length of polymer chain required for SC formation disclosed by Bertin.
A lactic acid polymer prodrug comprising gemcitabine connected via an amide bond is not disclosed.
Daman et al. discloses that gemcitabine hydrochloride (Gem) is a first line treatment for pancreatic cancer but acquired tumor resistance, a very short half-life with its most active metabolite being rapidly eliminated from the body with minimal antitumor activity are problems with this drug (¶ bridging cols 1 and 2 on p 142). A prodrug strategy has been widely employed to overcome the shortages associated with this drug to overcome resistance by enhancing cellular uptake through passive diffusion and improved pharmacokinetic behavior (p 142, col 2, ¶ 2). The 4-(N)-amino group of Gem is a favorable site for modification because the resulting amide derivatives have a slower rate of metabolism compared to esters derivatives on the 3’ and 5’ hydroxyl groups (p 142, col 2, ¶ 2). The therapeutic efficacy of these drugs requires a controlled delivery of the lipophilic chemotherapeutic agent to the tumor site so nanotechnology based drug delivery systems can be of great value because of not only their solubility enhancing properties but also passive and/or active targeting to the anticancer agent directly to the tumor site and reducing adverse effects (p 143, col 1, ¶ 1).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use the 4-(N)-amino group of Gem to prepare a SC prodrug with oligolactic acid as disclosed by Kruse et al. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Kruse et al. discloses that attachment to PLA oligomers can be used to prepare prodrugs and will alter properties such as the HLB balance of the drug, and given the desired slow release of Gem to exert anticancer activity, conjugation via an amide bond is preferred over ester bond formation and PLA can be used to form such a bond with gemcitabine. The preparation of a SC of the gemcitabine prodrug conjugate would reasonably be expected to further improve the properties of the drug releasing conjugates due to the enhanced thermal and mechanical properties and slower degradation rate of the SC compared to the constituent lactic acid oligomers/polymers.
The use of such gemcitabine prodrug stereocomplex as part of a micelle is not disclosed.
Tam et al. discloses the addition of drug (paclitaxel, PTX) conjugated to an oligo(lactic acid) (o(LA)) containing 8 or 18 units to micelles formed from poly(ethylene glycol)-block-poly(D,L-lactic acid) (PEG-b-PLA; whole document, e.g., abstract). While such micelles have been used due to their capacity for drug solubilization, low drug loading, poor stability against precipitation and burst drug release are issues (¶ bridging cols 1 and 2 on p 8674). The hypothesis that the use of the o(LA)n-drug conjugates with PEG-b-PLA micelles would result in higher loading and slower release compared to drug alone (p 8674, col 2, ¶ 3) was supported by the results shown in table 1 and figure 2. Drug delivery was increased and the o(LA)8-PTX induced tumor regression and less toxicity of body weight changes the free PTX (abstract). Adjusting the chain length of the o(LA)n can tune the release of the paclitaxel and the degradation product is two units of nontoxic D,L-lactic acid (p 8675, col 1, ¶ 1).
Chen et al. prepared micelles using an equimolar mixture of enantiomeric PLA-PEG block polymers that self-assembled into micelles in water (whole document, e.g., abstract). The critical micelle concentration (cmc) was lower and formed micelles were smaller than those formed using single PLLA-PEG or PDLA-PEG micelles (abstract and table 2).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to incorporate use the gemcitabine-oligolactic conjugate SC rendered obvious by Kruse et al., Bertin and Daman et al. into micelles prepared using PEG-b-PLA disclosed by Tam et al. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Tam et al. discloses that drugs conjugated to o(LA) can be used in combination with micelles formed from PEG-b-PLA and Chen et al. discloses that one of ordinary skill in the art would reasonably expect that stereocomplexes of such conjugates could be used in combination with micelles as the stereocomplex can be used to form micelles at even lower concentrations then polymer containing a single enantiomer of lactic acid. This would provide the stereocomplex of the gemcitabine prodrug in a nanotechnology based drug delivery systems as suggested by Daman et al.
Chen et al. uses similar methodology for micelle formation (see p 779, col 1, ¶ 3 and col 2, ¶ 3) as in the instant application (¶ [0071] of the PGPub of the instant application) which will determine the exact localization of the SC in the final micelles even though the instant claims are not product-by-process claims. Explicit appreciation in the prior art of the localization of the ingredients in the final micelles is not required to render the instant claims obvious. When the stereocomplex is loaded in the micelles as cargo, by definition the stereocomplex must be associated with oligolactic acid in the core as the oligolactic acid is an integral part of the stereocomplex which cannot form in the absence of the oligolactic acid.
The listing of gemcitabine derivatives at the end of claim 24 does not require the use of one of the derivatives but rather is limiting the scope of gemcitabine derivative in the claim limitation “conjugate of gemcitabine or a gemcitabine derivative” recited earlier in the claim.
Applicants traverse this rejection on the grounds that there is no motivation to combine and no reasonable expectation of success in combining the above references to deliver a water soluble drug that is loaded inside the core of a micelle and asserting otherwise relies on impermissible hindsight. Kruse and Daman fail to disclose stereocomplexes. The ester bond is Kruse fails to suggest the free COOH and amide bond for gemcitabine attachment as claimed. Three methods of micelle formation are taught in Daman, with solvent evaporation showing higher drug loading and encapsulation efficiency compared to the other two methods. One of ordinary skill in the art considering Daman would appreciate that amide bond formation in the prodrugs includes mere attachment of GemC18 to OLA. None of the stereocomplexes in Bertin are attached to an active pharmaceutical ingredient (API) and most are part of block copolymers used to form micelles and other nanoparticles. Drug release in Bertin is entirely based on release of unconjugated drugs from a nanostructure formed from polymers capable of forming stereocomplexes. The API is associated with the oligolactate stereocomplex and there is no guidance in Bertin to use the stereocomplex as a prodrug, let alone the specifically claimed prodrug. One of ordinary skill in the art when considering the disclosures of Kruse, Daman and Berting would not have possessed motivation to prepare the stereopure OLA conjugates necessary for SC formation because doing so would change the principle of operation in Bertin and such modifications are not sufficient to render the claims prima facie obvious. Bertin teaches chiral OLA moieties can form SCs and all the advantages mentioned by Bertin relate specifically to the nanostructures that could not be formed without larger polymer so no technical basis exists for assuming the claimed OLA-Gem stereocomplex would exhibit the same advantageous properties.
These arguments are unpersuasive. That no single reference teaches all the claimed features is why the rejection is made over a combination of references. Ibuprofen is a model drug in Kruse for investigation of synthesis methodology and first biological data assessment (p 93, col 2, ¶ 2). Changed HLB (hydrophilic-lipophilic balance) is amongst the reasons given for prodrugs to individualize prodrug properties with “[t]ypical prodrug moieties are e.g. long lipid chains that enhance lipid solubility” (emphasis added; p 93, col 1). While not a lipid, lactic acid is hydrophobic in nature and would enhance lipid solubility, particularly for a water soluble drug such as gemcitabine. Enhanced lipid solubility from such a group would reasonably suggest to one of ordinary skill localization in the hydrophobic core of a micelle, particularly in comparison to the non-oligolactic acid containing prodrug form of a hydrophilic drug. A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton (MPEP 2141(II)(C). Different drugs have different functional groups that can be used for conjugation purposes. Particularly in light of the explicit teachings of Daman as to the favorability of the 4-(N)-amino group of gemcitabine for modification to produce amide derivatives with slower rates of metabolism compared to esters, one of ordinary skill in the art would have been motivated to prepare a gemcitabine prodrug as in Kruse with an amide bond using a carboxylic acid group from the oligolactic acid that would have slower metabolism that an ester containing compound that would also have enhanced lipid solubility compared to the free drug form. "The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference .... Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art." In re Keller, 642 F.2d 413,425 (CCPA 1981) MPEP 2145(III) Bertin is cited for teachings relating to stereocomplex formation and does not require modification of the drug release mechanism that may also be discussed in Bertin. Covalent conjugation with drug release caused by bond cleavage is taught by Krusa and Daman. Applicants have not presented any persuasive arguments or evidence that one of ordinary skill in the art would not reasonably expect that a stereocomplex of lactic acid would not, for example, exhibit “a slower degradation rate compared to the individual homopolymers” taught by Bertin (p 2330, col 1, ¶ 1) as by definition, the stereocomplex must contain two individual homopolymers. Further association into a higher level structure with more polymer chains could results in further slowing of the degradation rate but the statements of record do not rise to the level of establishing a lack of motivation to prepare a stereocomplex of an OLA prodrug comprising gemcitabine. The instant claims do not exclude nanostructures comprising the stereocomplex from being the cargo loaded into the micelles. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., association of the API with the oligolactate stereocomplexes) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Rather the claims required covalent attachment, via an amide bond, of the gemcitabine API to the oligolactic acid and that conjugate forms the stereocomplex, so the API is not just associated with the stereocomplex but is covalently attached to the OLA material comprising the SC.
Applicants also argue that one of ordinary skill in the art considering Tam and Chen would not have possessed motivation to encapsulate water-soluble gemcitabine in a micelle since these references teach that micelles are carriers for poorly water soluble compounds. Tam mentioned the use of micelle carriers for paclitaxel given solubilization of this agent. PEG-b-PLA micelles are taught for the delivery of the hydrophobic moiety paclitaxel and help to solubilize the very hydrophobic drugs and also suggests that o(LA)s may be expanded to other poorly water soluble anticancer agents for enhanced delivery via PEG-b-PLA micelles. Tam fails to disclose or suggest using OLAs for water-soluble compounds and the claimed gemcitabine containing SC. Chen also relates to the sparingly water-soluble rifampin loaded PLLA/PDLA SC and also fails to teach or suggest the claimed SC. One of ordinary skill in the art would not have been motivated to load gemcitabine or a gemcitabine derivative inside a micelle to solubilize the highly soluble gemcitabine. It is necessary to identify a reason to modify a known compound in a particular manner in order to establish prima facie obviousness. As gemcitabine is not a poorly water soluble drug, the person of ordinary skill in the art would not have possessed motivation to adopt the strategy disclosed by Tam and Chen. Given the differences in water solubility, one of ordinary skill in the art would not have expected a gemcitabine OLA conjugated micelle to behave the same way as micellar compositions with hydrophobic drugs as in Tam and Chen.
These arguments are unpersuasive. The relevant question is not whether one of ordinary skill in the art would have been motivated to load PEG-b-PLA micelles with free gemcitabine or a derivative therefore but rather if one of ordinary skill in the art would have been motivated to load PEG-b-PLA micelles with gemcitabine or a derivative thereof conjugated to oligolactic acid in a SC. Neither the claims nor the rejection of record reiterated above require encapsulation of free gemcitabine in the micelles. Rather the claims require and the rejection provides motivation for the encapsulation of gemcitabine that is not only conjugated to oligolactic acid via an amide bond and with oligolactic acid portions having opposite stereochemistry to form a stereocomplex. Given the hydrophobic nature of oligo- and poly-lactic acids, one of ordinary skill in the art would not expect such a conjugate and SC comprising gemcitabine to be as highly water soluble as free gemcitabine. Kruse discusses that changes in HLB balance but also other altered properties such as improved resorption and cellular uptake, modulate organ specificity, achieve retarded drug action, increase plasma stability, modify metabolism or reduce toxicity from such prodrug formation. That motivates gemcitabine prodrug formation, whose properties can be further modified by the preparation of a SC as taught by Bertin. Then one of ordinary skill in the art would turn delivery of that prodrug SC. Tam and Chen prepare micelles of PEG-b-PLA that can be used for hydrophobic drugs such as paclitaxel or sparingly water soluble drugs. Applicants have not persuasively argued that one of ordinary skill in the art would not have reasonably expected success in being able to load the gem-OLA SC as cargo into a PEG-b-PLA micelle such as to achieve at least one of the benefits disclosed by references such as Tam et al. Solvent evaporation is the method used in the instant specification for micelle formation although that feature is not recited in the instant claims drawn to a product. Applicants’ arguments highlight that solvent evaporation is a known method as disclosed by Daman and Chen et al. uses similar methodology for micelle formation (see p 779, col 1, ¶ 3 and col 2, ¶ 3) which will determine the exact localization of the SC in the final micelles.
Applicants also argue that asserting that one could combine references is hindsight bias as it fails to address whether one of ordinary skill in the art would be motivated to make the combination. Without the present disclosure as a guide, it would not be obvious to one having ordinary skill in the art to modify the prodrugs od Kruse to form SCs, let alone modify the prodrugs of Kruse with the particular selections necessary to arrive at the SCs of the present invention.
These arguments are unpersuasive. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Motivation to combine the references was previously set forth and is reiterated above. Applicants’ arguments regarding the motivation set forth are not persuasive.
Applicants also argue that even there is motivation to combine the applied references with a reasonable expectation of success, the claimed stereocomplexes are surprisingly and unexpectedly effective for use in micelles. SC (o(L+DLA)10-GEM) loaded micelles showed no drug release for over 168 hours and was gradually release with a t1/2 of about 60 hours in the first 3 days, in sharp contrast to the release of non-stereocomplexed OLA conjugates that were released too quickly. GEM is the only major degradation species in plasma after 24 hours from the SC while the non-SC complexes o(LLA)10-GEM and o(DLLA)10-Gem rapidly degraded in plasma due to esterases and backbiting that even in phosphate buffer resulted in a range of intermediates as well as GEM. The above advantages translate to better in vivo efficacy at lower doses when in a mouse model system. There results are entirely unexpected in view of the combination of the cited art and the hydrophilic nature of gemcitabine.
These arguments are unpersuasive. The data presented indicate the different forms such as the gem-OLA prodrug alone and the SCs do not behave in the same manner. The question is whether those differences are in fact unexpected. Applicants do not establish what the expected results would be and the burden is on Applicant to explain the evidence offered in support of allegations of unexpected results (see MPEP 716.02 et seq. for a complete discussion of unexpected results). For example, Bertin discloses that stereocomplexes have a slower degradation rate compared to the individual homopolymers (p 2330, col 1, ¶ 1) and even with just two polymer chains of a SC not assembled in a higher level structure, the motion of each polymer chain, required for a backbiting reaction intramolecular reaction to occur, would be reduced. Assembly of SCs into higher level structures such as nanoparticles would likely further reduce such motion to further reduce the expected rate of backbiting but it seems reasonable to conclude that even a single SC would have an altered rate of backbiting. Without explanation as to what the expected results would be in relation not just free gemcitabine but also after conjugation to a hydrophobic oligolactic acid unit, it cannot be determined if the results of record are in fact unexpected. Evidence of unexpected results must also be reasonably commensurate in scope with the claims. No explanation as to how the single construct with 10 lactic acid subunits would then behave in a predictable manner across the entire claimed range of 7 – 20 lactic acid subunits has been provided to assist in any persuasive evidence also being reasonably commensurate in scope with the claims.
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.
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Applicants traverse the nonstatutory double patenting rejections on the grounds that the claims of US’471 and US’891 are directed to oligolactic conjugates of paclitaxel, rapamycin and selumetinib and micelles loaded with such conjugates. Each of those drugs are hydrophobic, which is in contrast to the hydrophilic gemcitabine. The patents are not drawn to micelles loaded with a stereocomplex of gemcitabine conjugated to oligolactic acid. Different therapeutics and different types of OLA conjugates are involved. These differences and the deficiencies of Bertin, Daman, Chen and Tam discussed above fail to render the present claims obvious in view of the cited claims.
These arguments are unpersuasive. The addition of an oligolactic group will alter the HLB of a drug such as gemcitabine. While the exact same structures are not claimed in either US’471 and US’891 as claimed in the instant application, the teachings of the additional references and the knowledge of one of ordinary skill in the art renders obvious the instant claims that require a conjugate of the water soluble gemcitabine with a hydrophobic oligolactic acid group despite the differences with the claims of US’471 and US’891.
Claims 24 – 30, 39 and 40 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 - 25 of U.S. Patent No. 10,456,477 in view of Bertin (Macromol Chem Phy, 2012) and Daman et al. (Int J Pharm, 2014) further in view of Tam et al. (JACS, 2016) and Chen et al. (J Nanoparticle Res, 2007). This rejection is MAINTAINED for the reasons of record set forth herein.
The claims of US’477 comprise oligolactic acid conjugates with the anticancer drugs paclitaxel, rapamycin, selumetinib or derivatives thereof with 2 – 24, or most narrowly 6 – 18, lactic acid units (claims 1 and 3) and compositions such as micelles that comprise such an oligolactic acid conjugates. Methods of preparing and using such conjugates are also claimed.
Stereocomplexes of the oligolactic acid with the anticancer drug gemcitabine attached are not claimed.
Bertin and Daman et al. are discussed above.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to replace the anticancer agents of the conjugates of US’477 with gemcitabine in light of teachings of Daman et al. and to prepare a SC with a complementary gemcitabine containing PLA conjugate. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Bertin discloses the improved properties arising from PLA SC formation, such as that prepared from a 1:1 mixture of the D- and L-enantiomers of lactic acid. At least 7 such units are required for SC complex formation and the materials of US’477 are suitable for such SC formation. Based on the knowledge of the person of ordinary skill in the art and the teachings of Daman et al., it also would have been obvious to replace the anticancer agents of the oligolactic acid conjugates claimed by US’477 with gemcitabine conjugated via an amide bond formed using the 4-(N)-amino group of Gem given the slower metabolism compared to esters formed using other positions on the Gem. The selection of the particular anticancer agent depends on the type of cancer to be treated among other factors and the anticancer agent to be used can be selected by the person of ordinary skill in the art.
The use of such a material as part of a micelle is not claimed.
Tam et al. and Chen et al. are discussed above.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to incorporate use the gemcitabine-oligolactic conjugate rendered obvious by US’477, Bertin and Daman et al. into micelles prepared using PEG-b-PLA disclosed by Tam et al. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Tam et al. discloses that drugs conjugated to o(LA) can be used in combination with micelles formed from PEG-b-PLA and Chen et al. discloses that one of ordinary skill in the art would reasonably expect that stereocomplexes of such conjugates could be used in combination with micelles as the stereocomplex can be used to form micelles at even lower concentrations then polymer containing a single enantiomer of lactic acid. This would provide the stereocomplex of the gemcitabine prodrug in a nanotechnology based drug delivery systems as suggested by Daman et al.
Claims 24 – 30, 39 and 40 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 - 20 of U.S. Patent No. 10,980,891 in view of Bertin (Macromol Chem Phy, 2012) and Daman et al. (Int J Pharm, 2014) further in view of Chen et al. (J Nanoparticle Res, 2007). This rejection is MAINTAINED for the reasons of record set forth herein.
The claims of US’891 recite oligolactic acids conjugates with the anticancer drugs paclitaxel, rapamycin, selumetinib or derivatives thereof (e.g., claim 1). A micelle composition with such conjugates and a polymer such as PEG-b-PLA are also claimed.
Stereocomplexes of the oligolactic acid with the anticancer drug gemcitabine attached are not claimed.
Bertin and Daman et al. are discussed above.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to replace the anticancer agents of the conjugates of US’891 with gemcitabine in light of teachings of Daman et al. and to prepare a SC with a complementary gemcitabine containing PLA conjugate. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Bertin discloses the improved properties arising from PLA SC formation, such as that prepared from a 1:1 mixture of the D- and L-enantiomers of lactic acid. At least 7 such units are required for SC complex formation and the materials of US’891 are suitable for such SC formation. Based on the knowledge of the person of ordinary skill in the art and the teachings of Daman et al., it also would have been obvious to replace the anticancer agents of the oligolactic acid conjugates claimed by US’891 with gemcitabine conjugated via an amide bond formed using the 4-(N)-amino group of Gem given the slower metabolism compared to esters formed using other positions on the Gem. The selection of the particular anticancer agent depends on the type of cancer to be treated among other factors and the anticancer agent to be used can be selected by the person of ordinary skill in the art.
While micelles containing the oligolactic acid drug conjugate are claimed, the use of a stereocomplex in such micelles is not claimed.
Chen et al. is discussed above.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to incorporate use the gemcitabine-oligolactic conjugate stereocomplex rendered obvious by US’477, Bertin and Daman et al. into micelles such as those comprised of PEG-b-PLA. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Chen et al. discloses that micelles formed from PEG-b-PLA and lactic acid stereocomplexes will form micelles at even lower concentrations then polymers containing a single enantiomer of lactic acid. Therefore the stereocomplex formation would reasonably be expected not to interfere with micelles preparation by one of ordinary skill in the art.
Conclusion
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/Nissa M Westerberg/Primary Examiner, Art Unit 1618