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 .
Applicant’s amendments, filed 8/25/2025, is acknowledged.
Claims 2, 3, 8, 11, 12, 14, 16, and 20-25 are cancelled.
Claims 1, 4-7, 9, 10, 13, 15, 17, 18, and 19 are currently pending.
Election/Restrictions
It is noted that Applicant has clarified the repository codes of the hybridomas producing the claimed antibody clones (remarks filed 8/25/2025, pg. 19):
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The elected species of antibody, clone DWP, has the DSZM code ACC3359, as well as the CDR sequences disclosed in the instant specification, pg. 11, lines 15-22, and recited in instant claim 9.
Claims 10, 17, and 18 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions and/or species.
Claims 1, 4-7, 9, 13, 15, and 19 are currently pending.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 8/25/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner in its entirety.
Biological Deposit
The reference to the previous deposit of the hybridomas producing the antibody clones DWP, D113, and D210 in U.S. Patent No 5,084,380 is confirmed. These hybridomas have the ATCC repository codes supra. This information is disclosed in the instant specification on pg. 9, lines 9-30.
Additionally, the statement for deposit of DSM ACC3358 and DSM ACC3359 has under the Budapest Treaty is disclosed in Applicant’s arguments filed 8/25/2025 on pg. 19 and 20.
The requirements for the biological deposit under 37 CFR 1.801-1.809 of the hybridomas recited in instant claim 1 have been satisfied.
Response to Arguments/Amendments
Applicant has demonstrated the Cadete Pires et al. (Pharmacology. Université d’Angers; Universidad de Santiago de Compostela. Facultad de Farmacia, 2016. English. NNT: 2016ANGE0071, in Office Action mailed on 2/26/2025, on IDS submitted 8/25/2025) was released under two different versions, and the later version, published after the effective filing date of the instant application, was relied upon for the previous 35 U.S.C. 103 rejection in the Office Action mailed 2/26/2025.
Due to this, the previous 35 U.S.C. 103 rejections have been withdrawn. Applicants arguments to these rejections, filed 8/25/2025, have been rendered moot.
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.
Claims 1, 5-7, 9, 15, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Szafraniec et al. (Nanoscale. 2017 Dec 7;9(47):18867-18880. doi: 10.1039/c7nr05851a) in view of Choi et al. (Biomaterials. 2010 Jan;31(1):106-14. doi: 10.1016/j.biomaterials.2009.09.030. Epub 2009 Sep 26), Sun et al. (Wound Repair Regen. 2010 May-Jun;18(3):302-10. doi: 10.1111/j.1524-475X.2010.00591.x. Epub 2010 Apr 15), Carney (U.S. Patent 5,443,956, also in Office Action mailed 2/26/2025 and on IDS submitted 3/02/2022), and Shin et al. (Nat Commun. 2017 May 10;8:15090. doi: 10.1038/ncomms15090).
Shin et al. is used as reference teaching motivation to target oncogenic Ras in tumors. Shin et al. teaches that oncogenic Ras, including oncogenic KRas (i.e., “activated mutated KRAS proteins”) are commonly mutated in human cancers (first ¶ of pg. 2): “[o]ncogenic Ras mutants, and most frequently KRas mutants (86% of Ras-driven cancers), are found in ~25% of human cancers…”
Shin et al. additionally teaches that a challenge in antibody-based targeting of oncogenic Ras, which is located in the cytosol, as (third ¶ of pg.2): “…antibodies do not have the capacity to localize to cellular cytosolic regions after receptor-mediated endocytosis, restricting their therapeutic application in targeting cytosolic proteins…”. However, Shin et al. teaches that there is promise in targeting intracellular oncogenic Ras with antibodies, as intrabodies were developed that successfully inhibited tumor progression in mouse models (third ¶ of pg. 2). Shin et al. additionally teaches (third ¶ of pg. 2): “[t]his suggests that blocking intracellular RasGTP–effector PPIs using a conventional antibody regimen such as systemic administration could be an effective approach to inhibit oncogenic Ras-driven signalling (sic).”
Shin et al. is provided to demonstrate that there is an overarching motivation to target intracellular Ras with antibodies to inhibit tumor progression in Ras-driven tumors, especially given that oncogenic Ras is present in about 25% of all cancers. Shin et al. also teaches that there is promise in using antibodies to target oncogenic Ras.
Szafraniec et al. teaches oil-core HA-coated nanocapsules (Abstract and Figure 2 below):
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These nanocapsules comprise an oil inner core, and an outer shell comprising HA linked to a hydrophobic moiety (see Figure 2 above, “Hydrophobically modified hyaluronate”; i.e., the limitations of instant claim 15). These nanoparticles were shown to have limited toxicity in vivo (Sections 2.9 and 3.4). Additionally, the nanoparticles were able to encapsulate the hydrophobic Nile red and rhodamine B dyes for imaging studies (Section 2.4), and were found to be taken up by cells in the liver and lungs of mice (i.e., intracellular delivery, Section 3.3 and Figure 6). Szafraniec et al. concludes (Conclusion): “[i]n summary, the proposed core–shell nanocapsules were shown to serve as a potential nanodelivery system for lipophilic compounds”.
Szafraniec et al. additionally teaches pharmaceutical compositions comprising the nanocapsules and the acceptable carrier saline for injection into subjects such as mice (i.e., the limitations of instant claim 19; Szafraniec et al. Sections 2.4 and 2.6).
Szafraniec et al. therefore teaches a compositions comprising a plurality of nanocapsules with an outer shell and an inner core. The outer shell comprises HA, and the inner core comprises an oil.
Szafraniec et al. does not teach the nanoparticles further comprising an antibody, or one of the antibodies recited in instant claim 1.
Choi et al., in the same field of endeavor, teaches spontaneously forming nanocapsules comprising an HA shell and an inner core comprising cholanic acid for intracellular drug delivery (Abstract). Choi et al. additionally teaches the conjugation of a Cy5.5 fluorescent molecule to the HA (Section 2.2 and Figure 1, annotated below; arrow points to the Cy5.5 conjugated to HA):
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Choi et al. additionally teaches that these nanoparticles were capable of intracellularly delivering the Cy5.5 to tumor cells both in vitro (Figure 3) and in vivo (Figure 4). Thus, Choi et al. teaches that conjugation of compounds to HA coated nanoparticles will lead to intracellular delivery of that compound into a cell, such as a tumor cell.
Neither Choi et al. nor Szafraniec et al. teach successful conjugation of antibodies to HA.
Sun et al., in the same field of endeavor, teaches conjugation of hyaluronic acid to two monoclonal antibodies, one specific to IL-1β and one to TNFα (Abstract). Sun et al. teaches a method of conjugating antibodies to hyaluronic acid that one with ordinary skill in the art would be able to use (“HA–RGD and HA–RGD–mAb preparation” Section).
None of the references discussed supra teach the anti-KRas-G12V DWP antibody clone.
Carney, in the same field of endeavor, teaches the anti-active mutant KRAS antibody clone DWP obtained from the hybridoma with the designation of ATCC-HB8698 DWP (Col. 10 line 66 to Col. 11, line 2, Claim 2). This antibody binds mutated KRAS with the G12V constitutively active point mutation (i.e., instant SEQ ID NO: 40), which meets the limitations of claims 5-7.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the instant invention, to have combined the Szafraniec et al. in view of Choi et al., Sun et al., Carney, and Shin et al., to have made a nanocapsule comprising an oil core and an HA shell with the anti-KRAS-G12V antibody DWP conjugated to the HA, allowing for intracellular delivery of the antibody, with a reasonable expectation of success. First, Shin et al. established motivation to attempt to engineer therapeutics that allow for intracellular delivery of antibodies that bind to oncogenic Ras such as KRas-G12V, as about 25% of cancers express oncogenic Ras. Szafraniec et al. teaches nanocapsules comprising an oil core and an HA shell that are taken up by cells. Choi et al. teaches that compounds such as Cy5.5 can be conjugated to the HA shell, which will also be taken up by cells upon exposure. One with ordinary skill in the art would appreciate that the HA shell of the nanocapsules taught by both Szafraniec et al. and Choi et al. can have compounds conjugated to it such as Cy5.5, as these are the same HA molecules and therefore the same conjugation techniques can be used.
Additionally, Sun et al. established that antibodies can also be conjugated to HA, and teaches a method of doing so; and Carney teaches the DWP anti-KRAS-G12V antibody clone that binds to oncogenic KRAS. One with ordinary skill in the art would appreciate that compounds other than Cy5.5 can be conjugated to HA, and then this conjugate can be used to form a nanocapsule as well, such as the one taught by Szafraniec et al. Therefore, one with ordinary skill in the art would have a reasonable expectation of success of making a plurality of nanoparticles comprising an inner oil core surrounded by an outer shell comprising HA conjugated to the anti-KRas-G12V antibody clone DWP in light of the combined teachings of Szafraniec et al. in view of Choi et al., Sun et al., and Carney. One would have been motivated to make this for the purposes of engineering a therapeutic that allows for antibody targeting of intracellular oncogenic KRas, as taught by Shin et al.
Regarding instant claim 9, although the Carney reference does not teach the sequences for the CDRs from the DWP monoclonal antibody, these are intrinsic properties of the DWP antibody. Also, it is an inherent property of the DWP immunoglobulin light and heavy chains to bind to the same antigen as the original antibody. Therefore, the light and heavy chain CDRs instantly claimed are unpatentable over the prior art as the sequences are intrinsic properties of the antibody.
The Courts have held that there is no requirement that those of ordinary skill in the art know of the inherent property. See MPEP 2131.01(d) and MPEP 2112 - 2113.
The issues presented herein are akin to the holding in In re Crish, 73 USPQ2d 1364 (CAFC 2004) where the Federal Circuit held that the claimed promoter sequence obtained by sequencing a prior art plasmid that was not previously sequenced was anticipated by the prior art plasmid which necessarily possessed the same DNA sequence as the claimed oligonucleotides. The court stated that “just as the discovery of properties of a known material does not make it novel, the identification and characterization of a prior art material also does not make it novel.”
Like the references in Crish, the prior art of Carney discloses a material containing the same sequence recited in the claims. It is undisputed that Carney teaches an antibody that contains the amino acids recited in Applicant’s claim 9. That disclosure is anticipatory, even if it was not until the present application that Applicants characterized Mab DWP by its amino acid sequences.
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.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Szafraniec et al. (supra) in view of Choi et al. (supra), Sun et al. (supra), Carney (supra), and Shin et al. (supra), as applied to claims 1, 5-7, 9, 15, and 19 above, and further in view of Safdari et al. (Biotechnol Genet Eng Rev. 2013;29:175-86. doi: 10.1080/02648725.2013.801235, in Office Action mailed 2/26/2025).
The teachings of Szafraniec et al. in view of Choi et al., Sun et al., Carney, and Shin et al., have been discussed supra. The combined teachings do not teach a humanized antibody (the limitations of instant claim 4).
Safdari et al. in the same field of endeavor, teaches than the human immune response neutralizes administered non-human antibodies in patients, which limits the application of such antibodies in the treatment of human diseases (Introduction). Safdari et al. teaches that there are multiple known techniques to “humanize” antibodies to overcome this limitation, such as CDR grafting onto human frameworks and germline humanization (pages 175-177).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the invention, to have modified the combined teachings of Szafraniec et al. in view of Choi et al., Sun et al., Carney, and Shin et al., further in view of Safdari et al. to humanize the DWP anti-active KRAS to reduce the antibody’s immunogenicity in humans with a reasonable expectation of success, as Safdari et al. teaches multiple methods of antibody humanization. One would have been motivated to make this change for the purposes of reducing the immunogenicity of the DWP antibody taught by Carney when it is administered into humans.
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.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Szafraniec et al. (supra) in view of Choi et al. (supra), Sun et al. (supra), Carney (supra), and Shin et al. (supra), as applied to claims 1, 5-7, 9, 15, and 19 above, and further in view of Liang et al. (Biomaterials. 2015 Dec;71:11-23. doi: 10.1016/j.biomaterials.2015.08.035., in Office Action mailed 2/26/2025)
The teachings of Szafraniec et al. in view of Choi et al., Sun et al., Carney, and Shin et al., have been discussed supra. The combined references do not teach the compositions further comprising a tLyp-1 targeting moiety.
Liang et al. in the same field of endeavor, teaches a method of conjugating tLyp-1 to PEG (Figure 1) and generating nanoparticles/nanocapsules comprising a HA polymer shell, the tLyp-1 targeting moieties, and loaded pharmaceuticals such as doxacetal for the treatment of cancer (Scheme 1, Materials and Methods). These nanoparticles containing the tLyp-1 targeting moiety had a greater anticancer effect that nanoparticles without the tLyp-1, as seen in cytotoxic assays and cellular uptake assays (Results).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the invention, to have modified the combined teachings of Szafraniec et al. in view of Choi et al., Sun et al., Carney, and Shin et al. further in view of Liang et al. to add the tLyp-1 targeting moiety to the nanocapsules taught by the combined teachings of Szafraniec et al. in view of Choi et al., Sun et al., Carney, and Shin et al. with a reasonable expectation of success, as Liang et al. teaches modification of nanocapsules with HA shells to further comprise the tLyp-1 targeting moiety, which one with ordinary skill in the art would appreciate can be applied to any nanoparticle with an HA shell. One would have been motivated to make this change to increase the antitumor potency of the nanocapsules via the addition of the tLyp-1 targeting moiety, as taught by Liang et al.
Therefore, the invention as a whole was prima facia 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.
Claims 1, 5-7, 9, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Fernández et al. (U.S. Patent No. 9,415,019) in view of Carney (supra) and Shin et al. (supra).
Shin et al. is provided to demonstrate that there is an overarching motivation to target intracellular Ras with antibodies to inhibit tumor progression in Ras-driven tumors, especially given that oncogenic Ras is present in about 25% of all cancers, as discussed supra.
Fernández et al. teaches (Col. 4, lines 1-10, emphasis added):
…nanocapsules comprise a polymer, an oil and a cationic Surfactant. These nanocapsular systems enable an effective partnership of lipophilic active ingredients and as well as hydrophilic ones. The Small size of said nanocapsules (diameter less than 1 um) allows passage through biological barriers and internalized by cells. Also, the presence of a polymeric shell, in addition to conferring greater stability to the nanocapsules, provides various beneficial characteristics depending on each particular type of shell.
Fernández et al. additionally teaches (Col 4, lines 32-54, emphasis added):
“In a further aspect, the invention is directed to a process for obtaining the above defined system (referred to in the examples solvent diffusion process in one stage), comprising:
a) preparing an aqueous solution comprising a polymer selected from the group consisting of polyglutamic acid (PGA), polyglutamic-polyethyleneglycol acid (PGA-PEG), hyaluronic acid (HA) and polyasparagine (PAsn) or a combination thereof, and optionally a water-soluble surfactant;
b) preparing an organic solution comprising an oil and a cationic surfactant, and optionally an oil-soluble surfactant;
c) mixing under stirring the solutions prepared in steps a) and b), spontaneously obtaining the nanocapsules, and
d) optionally, wholly or partially evaporating to constant volume the organic solvents from the mixture obtained in the previous stage.
According to particular embodiments, the encapsulation of a lipophilic active ingredient (hydrophobic) or amphiphilic is carried out by adding it in step b). The active ingredients of hydrophilic nature can be added in step a) of the process or at a stage later than stage d) through a process of incubation.”
Thus, Fernández et al. teaches nanocapsules comprising hydrophilic active ingredients for intracellular delivery of said active ingredient. Fernández et al. additionally teaches (Col. 16, lines 38-41): “…the active ingredient is selected from peptides, proteins…”. Fernández et al. additionally claims pharmaceutical compositions comprising the nanocapsules (claim 13-15).
Fernández et al. teaches multiple examples of the HA/oil nanocapsules (Example 5). Fernández et al. does not teach the nanocapsules comprising antibodies specific for oncogenic Ras such as clone DWP.
Carney, in the same field of endeavor, teaches the anti-active mutant KRAS antibody clone DWP obtained from the hybridoma with the designation of ATCC-HB8698 DWP (Col. 10 line 66 to Col. 11, line 2, Claim 2). This antibody binds mutated KRAS with the G12V constitutively active point mutation (i.e., instant SEQ ID NO: 40), which meets the limitations of claims 5-7.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the instant invention, to have modified the nanocapsules taught by Fernández et al. to encapsulate the anti-KRas-G12V antibody clone DWP taught by Carney et al., as Fernández et al. teaches methods of doing so (i.e., adding the antibody to the HA before mixing with the oil to form nanocapsules). One would have been motivated to do so to make a nanocapsule that is capable of intracellularly deliver the DWP clone to tumor cells that have oncogenic KRas-G12V as a therapeutic to inhibit tumor progression in Ras-driven tumors (see teachings of Shin et al. supra).
Regarding instant claim 9, although the Carney reference does not teach the sequences for the CDRs from the DWP monoclonal antibody, these are intrinsic properties of the DWP antibody. Also, it is an inherent property of the DWP immunoglobulin light and heavy chains to bind to the same antigen as the original antibody. Therefore, the light and heavy chain CDRs instantly claimed are unpatentable over the prior art as the sequences are intrinsic properties of the antibody.
The Courts have held that there is no requirement that those of ordinary skill in the art know of the inherent property. See MPEP 2131.01(d) and MPEP 2112 - 2113.
The issues presented herein are akin to the holding in In re Crish, 73 USPQ2d 1364 (CAFC 2004) where the Federal Circuit held that the claimed promoter sequence obtained by sequencing a prior art plasmid that was not previously sequenced was anticipated by the prior art plasmid which necessarily possessed the same DNA sequence as the claimed oligonucleotides. The court stated that “just as the discovery of properties of a known material does not make it novel, the identification and characterization of a prior art material also does not make it novel.”
Like the references in Crish, the prior art of Carney discloses a material containing the same sequence recited in the claims. It is undisputed that Carney teaches an antibody that contains the amino acids recited in Applicant’s claim 9. That disclosure is anticipatory, even if it was not until the present application that Applicants characterized Mab DWP by its amino acid sequences.
Therefore, the invention as a whole was prima facia 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.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Fernández et al. (supra) in view of Carney (supra) and Shin et al. (supra), as applied to claims 1, 5-7, 9, and 19 above, and further in view of Safdari et al. (supra).
The teachings of Fernández et al. in view of Carney and Shin et al. have been discussed supra. The combined teachings do not teach a humanized antibody.
Safdari et al. in the same field of endeavor, teaches than the human immune response neutralizes administered non-human antibodies in patients, which limits the application of such antibodies in the treatment of human diseases (Introduction). Safdari et al. teaches that there are multiple known techniques to “humanize” antibodies to overcome this limitation, such as CDR grafting onto human frameworks and germline humanization (pages 175-177).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the invention, to have modified the teachings of Fernández et al. in view of Carney and Shin et al. further in view of Safdari et al. to humanize the DWP anti-active KRAS to reduce the antibody’s immunogenicity in humans with a reasonable expectation of success, as Safdari et al. teaches multiple methods of antibody humanization. One would have been motivated to make this change for the purposes of reducing the immunogenicity of the DWP antibody taught by Carney when it is administered into humans.
Therefore, the invention as a whole was prima facia 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.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Fernández et al. (supra) in view of Carney (supra) and Shin et al. (supra), as applied to claims 1, 5-7, 9, and 19 above, and further in view of Liang et al. (supra).
The teachings of Fernández et al. in view of Carney and Shin et al. have been discussed supra. The combined teachings do not teach the nanocapsules additionally comprising a tLyp-1 targeting peptide (instant claim 13).
Liang et al. in the same field of endeavor, teaches a method of conjugating tLyp-1 to PEG (Figure 1) and generating nanoparticles/nanocapsules comprising a HA polymer shell, the tLyp-1 targeting moieties, and loaded pharmaceuticals such as doxacetal for the treatment of cancer (Scheme 1, Materials and Methods). These nanoparticles containing the tLyp-1 targeting moiety had a greater anticancer effect that nanoparticles without the tLyp-1, as seen in cytotoxic assays and cellular uptake assays (Results).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the invention, to have modified the combined teachings of Fernández et al. in view of Carney and Shin et al. further in view of Liang et al. to add the tLyp-1 targeting moiety to the nanocapsules taught by the combined teachings of Fernández et al. in view of Carney and Shin et al. with a reasonable expectation of success, as Liang et al. teaches modification of nanocapsules with HA shells to further comprise the tLyp-1 targeting moiety, which one with ordinary skill in the art would appreciate can be applied to any nanoparticle with an HA shell. One would have been motivated to make this change to increase the antitumor potency of the nanocapsules via the addition of the tLyp-1 targeting moiety, as taught by Liang et al.
Therefore, the invention as a whole was prima facia 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.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Fernández et al. (supra) in view of Carney (supra) and Shin et al. (supra), as applied to claims 1, 5-7, 9, and 19 above, and further in view of Szafraniec et al. (supra).
The teachings of Fernández et al. in view of Carney and Shin et al. have been discussed supra. The combined teachings do not teach the nanocapsules comprising polymers (i.e., the HA shell) linked to a hydrophobic moiety.
Szafraniec et al., in the same field of endeavor, teaches nanocapsules comprising an oil inner core, and an outer shell comprising HA linked to a hydrophobic moiety (see Figure 2 above, “Hydrophobically modified hyaluronate”; i.e., the limitations of instant claim 15). These nanoparticles were shown to have limited toxicity in vivo (Sections 2.9 and 3.4).
Szafraniec et al. teaches that the addition of the hydrophobic moiety to the HA stabilized the nanocapsules (Introduction and Section 3.2): “[i]n the present work we describe a surfactant-free technique for stabilization of capsules templated on liquid cores by hydrophobically modified HA”. Szafraniec et al. additionally teaches (Section 3.2): “for the capsules made of Hy-C18 the average size varies much less with time compared to the capsules stabilized with Hy-C6 and Hy-C8. This may indicate higher stability of the capsules with the shell having longer alkyl anchors”.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the instant invention, to have modified the teachings of Fernández et al. in view of Carney and Shin et al. further in view of Szafraniec et al. to add a hydrophobic moiety such as a 18 carbon long alkyl chain with a reasonable expectation of success, as Szafraniec et al. teaches methods of doing do (Section 2.3). One would have been motivated to make this change for the purposes of generating nanocapsules that have a higher stability.
Therefore, the invention as a whole was prima facia 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.
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.
Claims 1, 5-7, 9, and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 9,415,019 (herein Pat ‘019, supra) in view of Carney et al. (U.S. Patent 5,443,956, in Office Action mailed 2/26/2025 and on IDS submitted 3/02/2022, supra).
Pat ‘019 claims a compositions comprising nanocapsules having on oil core and an outer shell comprising HA (claim 1). Pat ‘019 additionally claims the nanocapsules comprising an active ingredient (claim 1), including peptides and proteins (claim 9). Pat ‘019 additionally claims pharmaceutical compositions comprising the nanocapsules (claim 13-15).
While Pat ‘019 claims the nanocapsules comprising proteins and peptides, it does not specifically claim the nanocapsules comprising antibodies or the antibodies recited in instant claim 1.
Carney, in the same field of endeavor, teaches the anti-active mutant KRAS antibody clone DWP obtained from the hybridoma with the designation of ATCC-HB8698 DWP (Col. 10 line 66 to Col. 11, line 2, Claim 2). This antibody binds mutated KRAS with the G12V constitutively active point mutation (i.e., instant SEQ ID NO: 40), which meets the limitations of claims 5-7.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the invention, to have modified the invention of Pat ‘019 in view of Carney to have made nanocapsules loaded with the anti-KRAS G12V antibody from ATCC-HB8698-DWP with a reasonable expectation of success, as Pat ‘019 claims the composition can comprise a protein or peptide. One would have been motivated to make this change for the purposes of creating a nanocapsule delivery mechanism to deliver the DWP antibody clone taught by Carney into a cell to treat mutant-KRAS driven cancers.
Regarding the functional limitations recited in instant claim 1, the functions recited in the wherein clauses of the claims flow naturally from the teachings of the prior art. (citing Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985 (“The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.”), and Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347 (Fed. Cir. 1999) (“[T]he discovery of... a scientific explanation for the prior art's functioning, does not render the old composition patentably new to the discoverer.”)).
An obvious formulation cannot become nonobvious simply by measuring and claiming an activity of the formulation in a particular context, “because ‘[t]o hold otherwise would allow any formulation—no matter how obvious—to become patentable merely by testing and claiming an inherent property.’” Persion Pharm., slip op. at 13 (Fed. Cir. Dec. 27, 2019) (citing Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344, 1354 (Fed. Cir. 2012)); see also Gen. Elec. Co. v. Jewel Incandescent Lamp Co., 326 U.S. 242, 249 (1945) (“It is not invention to perceive that the product which others had discovered had qualities they failed to detect.”).
Regarding instant claim 9, although the Carney reference does not teach the sequences for the CDRs from the DWP monoclonal antibody, these are intrinsic properties of the DWP antibody. Also, it is an inherent property of the DWP immunoglobulin light and heavy chains to bind to the same antigen as the original antibody. Therefore, the light and heavy chain CDRs instantly claimed are unpatentable over the prior art as the sequences are intrinsic properties of the antibody.
The Courts have held that there is no requirement that those of ordinary skill in the art know of the inherent property. See MPEP 2131.01(d) and MPEP 2112 - 2113.
The issues presented herein are akin to the holding in In re Crish, 73 USPQ2d 1364 (CAFC 2004) where the Federal Circuit held that the claimed promoter sequence obtained by sequencing a prior art plasmid that was not previously sequenced was anticipated by the prior art plasmid which necessarily possessed the same DNA sequence as the claimed oligonucleotides. The court stated that “just as the discovery of properties of a known material does not make it novel, the identification and characterization of a prior art material also does not make it novel.”
Like the references in Crish, the prior art of Carney discloses a material containing the same sequence recited in the claims. It is undisputed that Carney teaches an antibody that contains the amino acids recited in Applicant’s claim 9. That disclosure is anticipatory, even if it was not until the present application that Applicants characterized Mab DWP by its amino acid sequences.
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by Pat ‘019 in view of Carney, especially in absence of evidence to the contrary. This is a provisional nonstatutory double patenting rejection.
Claim 4 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 9,415,019 (Pat ‘019, supra) in view of Carney (supra), as applied to claims 1, 5-7, 9, and 19 above, and further in view of Safdari et al. (Biotechnol Genet Eng Rev. 2013;29:175-86. doi: 10.1080/02648725.2013.801235, in Office Action mailed 2/26/2025, supra)
The invention of claims 1, 5-7, 9, and 19 is an obvious variant of the invention claimed by Pat ‘019 in view of Carney, as discussed supra. Pat ‘019 in view of Carney does not claim a humanized antibody.
Safdari et al. in the same field of endeavor, teaches than the human immune response neutralizes administered non-human antibodies in patients, which limits the application of such antibodies in the treatment of human diseases (Introduction). Safdari et al. teaches that there are multiple known techniques to “humanize” antibodies to overcome this limitation, such as CDR grafting onto human frameworks and germline humanization (pages 175-177).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the invention, to have modified the teachings of Pat ‘019 and Carney further in view of Safdari et al. to humanize the DWP anti-active KRAS to reduce the antibody’s immunogenicity in humans with a reasonable expectation of success, as Safdari et al. teaches multiple methods of antibody humanization. One would have been motivated to make this change for the purposes of reducing the immunogenicity of the DWP antibody taught by Carney when it is administered into humans.
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by Pat ‘019 in view of Carney, and further in view of Safdari et al.
Claim 13 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 9,415,019 (Pat ‘019, supra) in view of Carney (supra), as applied to claims 1, 5-7, 9, and 19 above, and further in view of Liang et al. (Biomaterials. 2015 Dec;71:11-23. doi: 10.1016/j.biomaterials.2015.08.035., in Office Action mailed 2/26/2025, supra).
The invention of claims 1, 5-7, 9, and 19 is an obvious variant of the invention claimed by Pat ‘019 in view of Carney, as discussed supra. Pat ‘019 in view of Carney does not claim the nanocapsules additionally comprising a tLyp-1 targeting peptide (instant claim 13).
Liang et al. in the same field of endeavor, teaches a method of conjugating tLyp-1 to PEG (Figure 1) and generating nanoparticles/nanocapsules comprising a HA polymer shell, the tLyp-1 targeting moieties, and loaded pharmaceuticals such as doxacetal for the treatment of cancer (Scheme 1, Materials and Methods). These nanoparticles containing the tLyp-1 targeting moiety had a greater anticancer effect that nanoparticles without the tLyp-1, as seen in cytotoxic assays and cellular uptake assays (Results).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the invention, to have modified the invention claimed by Pat ‘019 in view of Carney further in view of Liang et al. to have added the tLyp-1 targeting moiety to the nanocapsules taught by the combined teachings of Pat ‘019 in view of Carney with a reasonable expectation of success, as Liang et al. teaches methods of conjugating tLyp-1 to nanocapsules with an HA shell. One would have been motivated to make this change to increase the antitumor potency of the nanocapsules via the addition of the tLyp-1 targeting moiety, as taught by Liang et al.
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by Pat ‘019 in view of Carney, and further in view of Liang et al.
Claim 15 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 9,415,019 (Pat ‘019, supra) in view of Carney (supra), as applied to claims 1, 5-7, 9, and 19 above, and further in view of Szafraniec et al. (Nanoscale. 2017 Dec 7;9(47):18867-18880. doi: 10.1039/c7nr05851a, supra).
The invention of claims 1, 5-7, 9, and 19 is an obvious variant of the invention claimed by Pat ‘019 in view of Carney, as discussed supra. Pat ‘019 in view of Carney does not claim the nanocapsules comprising polymers linked to a hydrophobic moiety.
Szafraniec et al., in the same field of endeavor, teaches nanocapsules comprising an oil inner core, and an outer shell comprising HA linked to a hydrophobic moiety (see Figure 2 above, “Hydrophobically modified hyaluronate”; i.e., the limitations of instant claim 15). These nanoparticles were shown to have limited toxicity in vivo (Sections 2.9 and 3.4).
Szafraniec et al. teaches that the addition of the hydrophobic moiety to the HA stabilized the nanocapsules (Introduction and Section 3.2): “[i]n the present work we describe a surfactant-free technique for stabilization of capsules templated on liquid cores by hydrophobically modified HA”. Szafraniec et al. additionally teaches (Section 3.2): “for the capsules made of Hy-C18 the average size varies much less with time compared to the capsules stabilized with Hy-C6 and Hy-C8. This may indicate higher stability of the capsules with the shell having longer alkyl anchors”.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the instant invention, to have modified the invention claimed by Pat ‘019 in view of Carney further in view of Szafraniec et al. to add a hydrophobic moiety such as a 18 carbon long alkyl chain with a reasonable expectation of success, as Szafraniec et al. teaches methods of doing do (Section 2.3). One would have been motivated to make this change for the purposes of generating nanocapsules that have a higher stability.
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by Pat ‘019 in view of Carney, and further in view of Szafraniec et al.
Claims 1, 5-7, 9, 13, 15, and 19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9, 11, 14, 31, 35, 39-42, 45, and 47-61 of copending Application No. 16/760,527 (herein App '527, in Office Action mailed 2/26/2025) in view of Carney et al. (supra).
App ‘527 claims a composition comprising a plurality of nanoparticles comprising an outer shell that comprises a polymer such as HA and an inner hydrophobic core that can comprise an oil (claim 1). App ‘527 additionally claims the nanoparticles can comprise a monoclonal antibody (claims 1 and 31) and targeting moieties such as tLyp-1 (claims 45, 47, and 48), the polymer linked to a hydrophobic moiety (claim 9), and pharmaceutical compositions (claim 59).
App ‘527 does not claim a composition wherein the antibody is an anti-active mutant KRAS antibody from one of the hybridomas recited in instant claim 1, or the limitations of instant claims 5-7.
Carney, in the same field of endeavor, teaches the anti-active mutant KRAS antibody clone DWP obtained from the hybridoma with the designation of ATCC-HB8698 DWP (Col. 10 line 66 to Col. 11, line 2, Claim 2). This antibody binds mutated KRAS with the G12V constitutively active point mutation (i.e., instant SEQ ID NO: 40), which meets the limitations of claims 5-7.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the invention, to have modified the invention of App ‘527 in view of Carney to have made nanocapsules loaded with the anti-KRAS G12V antibody from ATCC-HB8698-DWP with a reasonable expectation of success, as App ‘527 claims the composition can comprise an antibody. One would have been motivated to make this change for the purposes of creating a nanocapsule delivery mechanism to deliver the DWP antibody clone taught by Carney into a cell to treat mutant-KRAS driven cancers.
Regarding the functional limitations recited in instant claim 1, the functions recited in the wherein clauses of the claims flow naturally from the teachings of the prior art. (citing Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985 (“The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.”), and Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347 (Fed. Cir. 1999) (“[T]he discovery of... a scientific explanation for the prior art's functioning, does not render the old composition patentably new to the discoverer.”)).
An obvious formulation cannot become nonobvious simply by measuring and claiming an activity of the formulation in a particular context, “because ‘[t]o hold otherwise would allow any formulation—no matter how obvious—to become patentable merely by testing and claiming an inherent property.’” Persion Pharm., slip op. at 13 (Fed. Cir. Dec. 27, 2019) (citing Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344, 1354 (Fed. Cir. 2012)); see also Gen. Elec. Co. v. Jewel Incandescent Lamp Co., 326 U.S. 242, 249 (1945) (“It is not invention to perceive that the product which others had discovered had qualities they failed to detect.”).
Regarding instant claim 9, although the Carney reference does not teach the sequences for the CDRs from the DWP monoclonal antibody, these are intrinsic properties of the DWP antibody. Also, it is an inherent property of the DWP immunoglobulin light and heavy chains to bind to the same antigen as the original antibody. Therefore, the light and heavy chain CDRs instantly claimed are unpatentable over the prior art as the sequences are intrinsic properties of the antibody.
The Courts have held that there is no requirement that those of ordinary skill in the art know of the inherent property. See MPEP 2131.01(d) and MPEP 2112 - 2113.
The issues presented herein are akin to the holding in In re Crish, 73 USPQ2d 1364 (CAFC 2004) where the Federal Circuit held that the claimed promoter sequence obtained by sequencing a prior art plasmid that was not previously sequenced was anticipated by the prior art plasmid which necessarily possessed the same DNA sequence as the claimed oligonucleotides. The court stated that “just as the discovery of properties of a known material does not make it novel, the identification and characterization of a prior art material also does not make it novel.”
Like the references in Crish, the prior art of Carney discloses a material containing the same sequence recited in the claims. It is undisputed that Carney teaches an antibody that contains the amino acids recited in Applicant’s claim 9. That disclosure is anticipatory, even if it was not until the present application that Applicants characterized Mab DWP by its amino acid sequences.
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by App ‘527 in view of Carney, especially in absence of evidence to the contrary. This is a provisional nonstatutory double patenting rejection.
Claim 4 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9, 11, 14, 31, 35, 39-42, 45, and 47-61 of copending Application No. 16/760,527 (herein App '527, supra) and Carney (supra), as applied to claims 1, 5-7, 9, 13, 15, and 19 above, and further in view of Safdari et al. (supra)
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by App ‘527 in view of Carney, and further in view of Safdari et al. for the same reasons set forth for Pat ‘019 supra. This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
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