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 .
Election/Restrictions
Claims 1-6 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 9/8/25.
Polynucleotide (polynucleotide does not read on a CpG oligodeoxynucleotide because a polynucleotide encodes a protein and is not considered a non-coding sequence), Polyinosinic acid, polyICLC, lipopolysaccharide, muramyl peptide, lipoid A, a cytokine or any combination thereof in claim 9 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 9/8/25.
Response to Arguments
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Applicant’s arguments, see pages 4-7, filed 3/10/26, with respect to the rejection of claims 7-10 under 103 rejection have been fully considered and are persuasive. Therefore, the rejection has been withdrawn because of the amendment to independent claim 7 to recite “wherein carboxyl group of sodium alginate form a hydrogel and the water-soluble immunoadjuvant is encapsulated in the hydrogel”. However, upon further consideration, a new ground(s) of rejection is made in view of the amendment to claim 7.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 7-10 are rejected under 35 U.S.C. 103 as being unpatentable over Jarett (US 20160166504) taken with Sang Yong Jon (KR20110127995, see English translation, pages 1-28) and Rosenblum (US 20060263368) and Garcia-Astrain et al. (Carbohydrate Polymers 190 (2018) 271-289) in further view of Mo et al. (Nature Communications 5:3364, pages 1-10, 2013).
'504 claims a biomedical sustained release system comprising a first biodegradable material that is a hydrogel or a xerogel and a therapeutic agent, with the first material, before biodegradation, having a rate of release for the therapeutic agent as measured in physiological solution, and a second material that is a hydrogel or xerogel that at least partially coats the first material. Alternatively, an implant, medical device, drug depot, intraocular drug depot, fiber, xerogel fiber, a prosthesis, an object made to contact a physiological fluid, or a biomaterial comprising the first hydrogel or xerogel material is at least partially coated with the second material, wherein the therapeutic agent comprises a water-soluble biologic molecule and is an aptamer and the first hydrogel comprises solid particles of the aptamer (pages 16-20). Organic solvent gels (OSG) can be used in the system (pages 14-15). OSG can be made by cross-linking alginate gel with barium or calcium ion. '504 also teaches that sodium alginates form hydrogels upon contact with aqueous surroundings (page 2).
'504 does not specifically teach an immunoadjuvant-based hydrogel composition comprising a sodium alginate, a tumor cell death marker aptamer and a water-soluble immunoadjuvant with an extended sequence, wherein the sodium alginate is covalently attached to the aptamer by a peptide bond and the extended sequence is complementary to at least a part of the nucleotide sequence of the aptamer, and wherein the carboxyl groups of sodium alginate form a hydrogel, and the water-soluble immunoadjuvant is encapsulated in the hydrogel.
However, Sang Yong Jon teaches a carrier comprising a biocompatible polymer carrier; a first nucleic acid molecule covalently combined with the polymer; and a nucleic acid ligand and a composition comprising the polymer linked to the ligand, wherein the first nucleic acid molecule is a single stranded immunostimulatory CpG oligonucleotide (claims 1-10 on pages 23-24 of English translation). The CpG oligonucleotide comprises a sequence which is complementary to a sequence of the aptamer. The polymer can be alginate (page 13 of English translation).
In addition, Garcia-Astrain teaches that the carboxyl groups of sodium alginate are used to form a hydrogel (e.g., pages 271-272). See also MPEP 2141 II.C. Rationales to support rejections under 35 U.S.C. 103 recites, “Prior art is not limited to the references being applied, but includes the understanding of one of ordinary skill in the art.”
The pre-amble limitation 'immunoadjuvant-based hydrogel' in the claims does not add any structural limitations to the claim because the term is an inherent limitation of the structural limitations of the claims or an intended use of the composition. Also, the immunostimulatory oligonucleotide in an aqueous solution would read on the limitation in the pre-amble (see page 2 of '504).
Also, '504 teaches nucleotide aptamers are water-soluble and since an aptamer comprises oligonucleotides, then any oligonucleotide, including CpG oligonucleotides, would also be considered water-soluble (pages 17-20 of ‘504).
It would have been obvious to one of ordinary skill in the art to before the effective filing date to combine the teaching of '504 with Sang Yong Jon and Garcia-Astrain to make a composition comprising a polymer linked to an aptamer, wherein the polymer is sodium alginate; to deliver the aptamer to a cell or a subject. One of ordinary skill in the art would have been motivated to use sodium alginate as a drug delivery agent because it is found in nature and is a biocompatible drug delivery polymer. Also, a CpG oligonucleotide is hybridized to the aptamer via an extended sequence of the CpG oligonucleotide as taught by Sang Yong Jan. A person of ordinary skill in the art would have been motivated to indirectly link the oligonucleotides to the aptamer using an extended sequence of the oligonucleotide to avoid interfering with the activity of the aptamer and/or to allow substitution of a different immunoadjuvant using the extended sequence.
'504 taken with Sang Yong Jon and Garcia-Astrain do not specifically teach using a peptide bond to connect the aptamer to the sodium alginate.
However, '368 teaches making a composition comprising a chimeric conjugate with linkers, wherein the linker is a biologically-releasable bond, peptide linker (pages 18 and 74-75). The conjugate can comprise an aptamer that targets a tumor antigen (paragraphs 339-344). The composition can further comprise a carrier and can be sodium alginate (paragraph 354). When making a conjugate comprising the sodium alginate linked to the aptamer in the composition and one of ordinary skill in the art wanted to separate the sodium alginate from the aptamer they could use a peptide bond cleavable by a protease as taught by '368 to allow separation of the oligonucleotide from the aptamer in a cell. In addition, one of ordinary skill in the art could use an amino-modified aptamer or amino-modified alginate to make the peptide bond covalently linking the aptamer and the alginate to make alginate-ATP aptamer conjugate (pages 18-19 and 25 of '368).
'504, Sang Yong Jon, Garcia-Astrain and '368 do not specifically teach that the aptamer in the composition is a tumor cell death aptamer.
However, Mo et al. teach an ATP-driven drug release system for delivering anti- cancer agent, doxorubicin (DOX). See pages 1-8. The system was a nanogel comprising a DNA scaffold comprising an ATP aptamer and Cy5.5 labelled cDNA, which has a 27-base pair with GC-rich motif for anthracycline-contained Dox.
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of '504; Sang Yong Jon; Garcia-Astrain; '368 and Mo et al. to use an ATP aptamer as the aptamer in the composition, namely to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to combine the teaching to make the composition to deliver immunostimulatory oligonucleotides to cancer cells using the ATP aptamer to study treating cancer. Since a nanogel comprising an ATP aptamer can deliver a drug to cancer cells, it would have been obvious to try the nanogel to deliver CpG oligonucleotides to study immuno-stimulation of cancer cells. Since '504 teaches that sodium alginate is a biomedical sustained release hydrogel system for delivering an aptamer, it would have been a simple substitution to use sodium alginate to as the hydrogel to deliver the aptamer and an immunostimulatory oligonucleotide. See MPEP 2143(I)(B): Simple substitution of one known element for another to obtain predictable results. To make the composition, one of ordinary skill in the art could mix in a solution, an amino modified ATP aptamer and sodium alginate resulting in a conjugation comprising the two compounds linked via a peptide bond, then adding a CpG oligonucleotide comprising an extended sequence to the solution wherein the oligonucleotide hybridizes to the aptamer to make the claimed composition.
With respect to the new limitation ‘wherein carboxyl groups of sodium alginate form a hydrogel’, the limitation appears to be an inherent property of sodium alginate when placed into a solution because sodium alginate gels under neutral physiological conditions as taught by Garci-Astrain. See also MPEP 2141 II.C. Sodium alginate hydrogels are known for their carboxyl groups, which are essential for gelatin and cross-linking properties. For example, the carboxyl groups are involved in formation of cross-links with calcium ions, which are crucial for hydrogel’s mechanical strength and stability. The presence of carboxyl groups allows for the decoration of alginate with active agents (drugs, peptide, nucleic acids) enhancing its functionality in drug delivery systems.
With respect to the new limitation ‘the water soluble immunoadjuvant is encapsulated in the hydrogel” appears to directed to functional limitation of the claimed product and made obvious by pages 9-10 of Jarrett, which disclose that an active agent can be encapsulated in a biodegradable polymer. In addition, the limitation appears to be an inherent property of making the hydrogel composition. Jarrett, Jon, Garcia-Astrain, Rosenblum and Mo make obvious all of the claimed structural limitations, so the functional effects of the claimed product are considered to be inherent in the product taught by the prior art cited in the 103 rejection of record. Where, as here, the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product. See In re Ludtke 441 F.2d 660, 169 USPQ 563 (CCPA 1971). Whether the rejection is based on "inherency" under 35 USC 102, or "prima facie obviousness" under 35 USC 103, jointly or alternatively, the burden of proof is the same, and its fairness is evidenced by the PTO's inability to manufacture products or to obtain and compare prior art products. In re Best, Bolton, and Shaw, 195 USPQ 430, 433 (CCPA 1977) citing In re Brown, 59 CCPA 1036, 459 F.2d 531, 173 USPQ 685 (1972).
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Response to Arguments
Applicant's arguments filed 3/10/26 have been fully considered but they are not persuasive.
In response to applicant's argument that the examiner has combined an excessive number of references, reliance on a large number of references in a rejection does not, without more, weigh against the obviousness of the claimed invention. See In re Gorman, 933 F.2d 982, 18 USPQ2d 1885 (Fed. Cir. 1991). The rejection of record provides motivation and reasonably expectation of success for one of ordinary skill in the art to arrive at the claimed product. The rejection is under 103 and not 102. The structural elements are taught in the prior art and the 103 rejection of record provides motivation for making the claimed product with a reasonable expectation of success.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). This is the case here since the prior art teaches every structure of the claimed product, motivation was provided and there was a reasonable expectation to make the product. The combination of references is required because the rejection is under 103 and not 102. Each reference was required to show that each element of the product was known and/or provide a scientific fact and there was motivation to combine each element to arrive at the claimed invention.
'504 taken with Sang Yong Jon and Garcia-Astrain make obvious a composition comprising a polymer linked to an aptamer, wherein the polymer is sodium alginate; to deliver the aptamer to a cell or a subject. As taught by Sang Yong Jan, a CpG oligonucleotide is hybridized to the aptamer via an extended sequence of the CpG oligonucleotide. A person of ordinary skill in the art would have been motivated to indirectly link the oligonucleotides to the aptamer using an extended sequence of the oligonucleotide to avoid interfering with the activity of the aptamer and/or to allow substitution of a different immunoadjuvant using the extended sequence.
Rosenblum (‘368) was cited to show that peptide bonds are used to connect sodium alginate to a nucleic acid sequence (aptamer). Peptide bonds are biologically releasable bonds which would provide motivation to use these types of bonds in a cell.
Mo et al. teach a nanogel comprising a DNA scaffold comprising an ATP aptamer and Cy5.5 labelled cDNA. Mo et al. was cited to show that ATP aptamer was known in the prior art for treating cancer and can be paired to another nucleotide sequence.
Applicant argues that Jarett discloses a gel-loaded drug particle, where sodium alginate is an example and Jarett does not provide any specific examples and different gels can have different release rates. Thus, applicant argues that Jarett does not teach or suggest the claimed invention.
Applicant’s argument is not found persuasive because the rejection is under 103 and not 102. Jarret is combined with other references to make obvious the claimed invention. Pages 17-19 of Jarett specifically contemplates using a polymer selected from alginate, gelatin, collagen and polysaccharide as a biomedical sustained release system
The argument pertaining to gels having different release rates is not found persuasive because the combination of references provide motivation for one of ordinary skill in the art to use sodium alginate as a drug delivery vehicle.
In response to applicant’s argument that the a key difference between the claimed invention and the prior art cited in the 103 rejection is that the CpG (the active ingredient) is released in the microenvironment and exerts its immunostimulatory function, the argument is not found persuasive because the claimed invention is directed to a product and not a method of using the product. The structural limitations of the claimed product are made obvious by the prior art cited in the 103 rejection and the function of the product in a cell or subject would be considered an inherent property of the product made obvious by the 103 rejection.
Applicant further argues that Sang Yon Jen does not teach the separation of CpG from the polymer carrier or how the loaded drug is released and in Mo the main function of CpG is to absorb the drug (The GC pairs of the DNA motif provides faithful loading sites for Dox, paragraph 3 of Mo).
The argument is not found persuasive because CpG oligonucleotides were known in the prior art to provide an immunostimulatory effect to treat cancer. Mo was cited to show that the ATP aptamer was well known in the prior art for treating cancer. In addition, the applicant is arguing a use of the claimed product and not that it would not have been obvious to combine the references of record to make the claimed product.
Conclusion
See attached PTO-326 for disposition of claims.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brian Whiteman whose telephone number is (571)272-0764. The examiner can normally be reached on Monday thru Friday; 6:00 AM to 3:00PM.
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/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636
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