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 .
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.
Status of Claims
Claims 40-42 and 44-62 are pending. Claims 40-42, 44-47 and 61-62 are drawn to the nonelected inventions. Claims 1-39 and 43 are cancelled. Claims 48-60 are currently under examination.
Maintained Rejection
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries 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.
Claims 48-60 are rejected under 35 U.S.C. 103 as being unpatentable over Baumer et al. (“Antibody-coupled siRNA as an efficient method for in vivo mRNA knockdown”, Nature Protocols, vol. 11 (no. 1), pgs. 22-36, published 12/3/2015, of record 892 dated 03/07/2024) in view of Bourquin et al. (“Delivery of Immunostimulatory RNA Oligonucleotides by Gelatin Nanoparticles Triggers an Efficient Antitumoral Response” J Immunotherapy, vol. 33 (no. 9), pgs. 935-944, November-December 2010, of record 892 dated 06/20/2024) and Srikar et al. (“Targeted nanoconjugate co-delivering siRNA and tyrosine kinase inhibitor to KRAS mutant NSCLC dissociates GAB1-SHP2 post oncogene knockdown” Scientific Reports, vol. 6:30245, pgs. 1-14, published 08/17/2016, of record 892 dated 06/20/2024).
With respect to claims 48, 50, and 54, Baumer teaches chemically coupled cell surface receptor internalizing antibodies to the short interfering RNA (siRNA) carrier peptide protamine using the bispecific cross-linker sulfo-SMCC) (see abstract and Fig. 1). Baumer teaches in Fig. 1 linking the antibody to a macromolecule linker through an amide bond and the macromolecule linker electrostatically interactions with siRAN, which would read on a process for preparing a conjugate comprising Formula (1), An wherein n = 1 and Lx wherein x = 1 and By y = 1-3. Baumer teaches in Fig. 1 that the macromolecule linker is a protamine (cationic) and siRNA is anionic. In particular, Baumer teaches cetuximab (anti-EGFR mAb) is coupled to sulfo-SMCC-protamine (see Fig. 1, caption). Baumer teaches to target a certain cancer cell, one has to look for a surface marker and a specific antibody or antibody that binds to this surface protein and provokes the internalization of the antigen-antibody complex into the cells and the application of the complex is quite simple: cells can be incubated with it in culture…and the complex can be systemically injected into mice, leading to the inhibition of tumor growth in anti-EGFR-KRAS-siRNA-treated cell lines (see pg. 25, under Experimental design).
Even though Baumer teaches a macromolecule linker, the reference does not teach the macromolecule linker is a gelatin or modified gelatin and activation of said gelatin or modified gelatin at pH < 5 without any prior crosslinking step.
Bourquin teaches siRNA oligonucleotides with cationized gelatin nanoparticles and binding to gelatin nanoparticles protects RNA oligonucleotides from degradation by nucleases, facilitates their uptake by dendritic cells, and targets these nucleic acids to their endosomal compartment (see abstract; pg. 935, Summary; and Fig. 1). Bourquin teaches observing that RNA loaded onto the cationic nanoparticles surface was stable (see pg. 940, middle of left col.). Bourquin teaches to evaluate the physical stability of RNA oligonucleotide attachment to the cationic nanoparticle surface, dispersions were incubated in PBS at final pH of 7.4 or 4.9 for up to 1 week (see pg. 936, left col., last paragraph – right col., first paragraph). Bourquin teaches gelatin presents the advantage of being biodegradable and nontoxic and has been used in patients (see pg. 935, right col., last paragraph).
Srikar teaches a tri-block nanoparticle (TBN) comprising of an enzymatically cleavable porous gelatin nanocore with surface functionalized cetuximab-siRNA conjugate (abstract). Fig. 1 (a) shows cetuximab antibody is conjugated to siRNA and gelatin. Srikar further teaches for conjugating cetuximab monoclonal antibody on the surface of gelatin nanoparticle, carboxyl groups present on the surface were converted to reactive NHS ester followed by addition of antibody and the amine groups present in antibody reacted to the modified carboxyl group enabling the conjugation of the antibody to gelatin nanoparticle and subsequently, amine-thiol linker sulfo-SMCC was used (see pg. 2, last paragraph and pg. 11, siRNA functionalization section) which would be an amide bond. Srikar teaches thiol modified siRNA was added to the solution for linking the maleimide end to the linker to the thiol end of the siRNA (see pg. 11, siRNA functionalization section). Srikar teaches nanoparticles with appropriate controls including naked siRNA and Ab-Gel NP were added and naked siRNA and Ab-Gel NPs/GelGEFNPs were used as controls to evaluate the 24 hr stability of siRNA and electrostatically bound siRNA to nanoparticles had degradation profile similar to naked siRNA (see pg. 3, Stability of Tri-block Nanoparticle section). Srikar teaches synthesis of gelatin nanoparticles in DI water at pH 2.75 prior to the crosslinking step (see pg. 11, para. 1 of Materials and Methods). Additionally, Srikar teaches gelatin nanoparticles were suspended in MES buffer pH 4.5 and then activation was performed (see pg. 11, para. 2 of Materials and Methods). Gel NPs suspended in DI water showed a positive value of zeta potential (see pg. 3, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have produced the antibody-siRNA complex through cationic affinity as taught by Baumer with gelatin as taught by Bourquin and Srikar because (1) Bourquin teaches that gelatin is cationized for binding to siRNA and the cationized gelatin protects RNA oligonucleotides from degradation and (2) Srikar teaches that efficiency of gelatin covalently bound to antibodies via crosslinking. Because Bourquin teaches cationized gelatin has the advantage of being nontoxic, protects RNA degradation, and recognized in the art that gelatin conjugates RNA through charge attractions, it would have been obvious to the person to have replaced the cationic protamine with cationized gelatin for conjugating siRNA to antibody. Furthermore, it would have been obvious to have activated the gelatin or modified gelatin at pH < 5 because Srikar teaches gelatin is produced in pH 2.75 prior to a crosslinking step and Srikar and Bourquin recognize that gelatin is stable at pH < 5.
Additionally, the person would have produced the antibody-modified gelatin----siRNA complex through the process of pH <5 with Srikar’s antibody, cationic gelatin, and siRNA because Baumer teaches siRNA is attached to the cationic protein through charge attractions.
The person would have a reasonable expectation of success in attaching the cationized gelatin to the antibody via covalent attachment because it has been well recognized by Baumer and Srikar to use cetuximab antibody for covalent bonds.
With respect to claims 49 and 53, Baumer does not explicitly teach reacting an amine in A with amine reactive ester of L or reacting amine reactive ester of A with amine of L. Srikar teaches carboxyl groups present on the surface of gelatin were converted to reactive NHS ester (N-hydroxysuccinimide) followed by addition of antibody and the amine groups present in antibody reacted to the modified carboxyl group enabling the conjugation of the antibody to gelatin nanoparticle (see pg. 2, last paragraph and pg. 11, paras. 2-3 of Materials and Methods). Therefore, it would have been obvious to have the covalent reactions of Srikar because Baumer and Srikar recognize covalent reactions between antibodies and cationic proteins and it has been recognized in the art to use sulfo-SMCC for covalent conjugations.
With respect to claims 51-52, as stated above, Baumer does not teach gelatin or modified gelatin. Srikar teaches targeting antibody conjugated to KRASG12C (cysteine) siRNA by thio-ether linkage (see pg. 2, middle of paragraph 3) and SiRNA with disulfide (see pg. 2, middle of paragraph 3). It would have been obvious to have produced a thio-ether linkage or disulfide group because Srikar teaches producing thio-ether linkage or disulfide for covalent linking for siRNA attachment.
With respect to claim 55, as stated above, Baumer does not teach gelatin or cationic gelatin modified by one or more of synthetic modification selected from cleavage, chemical modification of carboxyl groups to amine groups or physical modification. Srikar teaches gelatin is a nanocore carboxyl groups present on the surface of gelatin were converted to reactive NHS ester (N-hydroxysuccinimide) or sulfo-SMCC followed by addition of antibody and the amine groups present in antibody reacted to the modified carboxyl group enabling the conjugation of the antibody to gelatin nanoparticle (see abstract and pg. 2, last paragraph). Therefore, it would have been obvious to have modified gelatin with amine groups for covalent reactions. It has been well recognized in the art to have modified functional groups for covalent reaction between molecules, as taught by Baumer and Srikar.
With respect to claim 56, Baumer does not teach the cationic gelatin is modified using EDC/NHS at a pH below 5. Srikar teaches the carboxyl group present on the surface of the Gel NPs and GelGEFNPs were activated using EDC/NHS (N-hydroxysuccinimide) reaction and the gelatin nanoparticles were suspended in MES buffer pH 4.5 (see pg. 11, under Cetuximab Conjugation). Therefore, it would have been obvious to have performed the EDC/NHS reaction on the gelatin nanoparticles for covalent and SMCC reactions.
With respect to claim 57, Baumer does not explicitly teach a pH is less then 11. However, it would have been obvious to have the antibody, antibody fragment, or peptide in physiological conditions for functional purposes.
With respect to claim 58, Baumer teaches cetuximab in a molecular excess of 23:1 to the macromolecule linker (see pg. 29, step 8).
With respect to claim 59, Baumer does not explicitly teach removal of excess of macromolecule linker and/or biomarker targeting moiety. Srikar teaches the particles were then washed to remove the supernatant containing unreacted antibody (see (see pg. 11, under Cetuximab Conjugation). It would have been obvious to have removed any excess because it contains the unreacted molecules.
With respect to claim 60, Baumer teaches siRNA (see abstract).
Response to Arguments
Applicant's arguments filed 12/30/2025 have been fully considered but they are not persuasive with respect to 35 U.S.C. 103 rejection over Baumer, Bourquin, and Srikar.
Applicant argues on page 6 of the Remarks that the cited references fail to teach or disclose or suggest “linking A to L chemically through an amide bond after activation of L at pH < 5 without any prior crosslinking step”. Applicant argues that the claim requires activation of L, gelatin and modified gelatin at pH < 5 to form amide bonds with antibody, antibody fragment, or peptide. Applicant argues pages 6-8 that (a) Baumer fails to disclose activation of L at pH < 5 or amide bonding of A to L; (b) Bourquin fails to disclose linking A to activated gelatin or activation without prior crosslinking and gelatin nanoparticles are pre-crosslinked; and (c) Srikar affirmatively teaches away from activation “without any prior crosslinking step”, as gelatin nanoparticles were crosslinked. Furthermore, Applicant argues on pages 9-11 that (d) examiner’s proposed combination lacks rational motivation and fails to teach the claimed process; and (e) unexpected result: solution to long-felt crosslinking failure.
The arguments are not found persuasive for the following reasons. The claim recites a broad linking step coupled with broad structures by reciting linking A to L chemically through an amide bond without specific chemical structures between A and L for amide bond formation. The claim does not identify the chemical structures of gelatin through merely the phrase activation of L. With respect to arguments of (b), (c), and (d 1-2), the structure of the claimed L is a macromolecule linker that is modified gelatin, which encompass gelatin nanoparticles. As acknowledged by Applicant, the recitation of “activation of L at pH < 5 without any prior crosslinking step” is a limitation for L (i.e., gelatin and modified gelatin). Thus, the claim does not exclude using a crosslinking step between linking A to L to form the amide bond because (1) no specific chemical structures have been identified to exclude a crosslinker, (2) limitation A does not exclude coupling with a crosslinker, and (3) the claim does not exclude crosslinking step after L at pH < 5, as linking B to L may be performed first at pH < 5. Secondly, Applicant has acknowledged under (A) that gelatin is a protein with both amines and carboxyls prone to self-crosslinking (see pg. 7, para. 2 of Remarks dated 12/30/2025). Therefore, the formation step of gelatin or modified gelatin would be prone to a self-crosslinking step. The interpretation of “activation of L at pH < 5 without any prior crosslinking step” would be inconsistent when encompassed producing gelatin or modified gelatin as they are prone to a self-crosslinking step. Thus, the limitation of “without any prior crosslinking step” has to be after the formation of gelatin or modified gelatin. Meanwhile, gelatin nanoparticle would read on the structure of “modified gelatin”.
As stated above, Baumer does not teach gelatin or modified gelatin but teaches cationic structures conjugating to antibodies. However, Srikar does teach modified gelatin (i.e., gelatin nanoparticle) were suspended in MES buffer pH 4.5 and conjugated to cetuximab antibody through carboxyl group of activated Gel NPs (EDC/NHS) (i.e., activated, see above or pg. 11, para. 2 of Materials and Methods). Srikar and Bourquin do recognize that modified gelatin activated by pH < 5 does not need additional prior crosslinking step. Thus, these references do not contradict or teach away from each other.
With respect to Applicant’s arguments to (d 3, see page 9), the arguments are not found persuasive. The rejection is not hindsight because first, Baumer teaches that its conjugate uses cationic for the attraction of siRNA, Bourquin teaches a similar concept of using cationic for siRNA attraction from modified gelatin with high stability at pH < 5, and Srikar teaches modified gelatin binds to antibody at pH < 5. Additionally, Srikar recognizes the use of covalent bond formation with and without a crosslinking group. Therefore, there is an understanding of forming covalent bonds through crosslinking groups and lack thereof.
Additionally, the person would have produced the antibody-modified gelatin----siRNA complex through the process of using modified gelatin pH <5 with Srikar’s antibody, cationic gelatin, and siRNA because Baumer teaches siRNA is attached to the cationic protein through charge attractions. In other words, the person would recognize that the formation of the modified gelatin nanoparticle with antibody of Srikar at pH < 5 would attracts siRNA. As noted above, the claim only recited “without any prior crosslinking” to L at pH < 5 limitation which does not exclude using a crosslinker between linking A to L to form the amide bond.
With respect to unexpected results, it is unpersuasive because Srikar does teach amide bond between gelatin and antibody at pH < 5. Meanwhile, the claims are directed to a process of making the conjugate and not using the conjugate in a particular reaction. Therefore, Applicant must show the produced structure (i.e., conjugate) that is providing the unexpected results disclosed from the instant specification. For example, the results are from a particular chemical structure of gelatin that has a specific amide bond to the antibody and only related to siRNA. Also, the arguments are unpersuasive because Applicant has not provided evidence that commensurate in scope with the claimed subject matter. To show unexpected results, the evidence must be (1) commensurate in scope with the claimed subject matter, In re Clemens, 622 F.2d 1019, 1035, 206 USPQ 289, 296 (CCPA 1980), (2) show what was expected, to "properly evaluate whether a … property was unexpected", and (3) compare to the closest prior art. Pfizer v. Apotex, 480 F.3d 1348, 1370-71, 82 USPQ2d 1321, 1338 (Fed. Cir. 2007).
As noted above, the claims do not exclude using a crosslinking step between linking A to L to form the amide bond (see above). Therefore, the obviousness rejection above is maintained.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/N.P.N/Examiner, Art Unit 1678
/SHAFIQUL HAQ/Primary Examiner, Art Unit 1678
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