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 .
Claims and Previous Objection/Rejections Status
Claims 1,2,4,6,9,16-19,21,22,28 and 32-37 are pending in the application. Claims 21,22,28 and 32-36 are withdrawn from further consideration.
Any objections and/or rejections from previous office actions that have not been reiterated in this office action are obviated.
Declaration/Affidavit
The declaration under 37 CFR 1.132 filed 4/27/26 is insufficient to overcome the rejection of claims 1,2,4,6,9,16-19 and 37 based upon 35 U.S.C. 103 as set forth in the last Office action because: the declaration states that the coated stents comprising a CoCr substrate material with a chromium oxide (Cr2O3) surface layer bound to 12-aminododecylphosphonic acid are associated with a 67% reduction in platelet adhesion (p [Symbol font/0x3C] 0.0005), an 84.8% reduction in neutrophil adhesion (p [Symbol font/0x3C] 0.005), and a 67.6% reduction in monocyte adhesion (p [Symbol font/0x3C] 0.001) wherein the instant claims are drawn to various metal oxide substrates that comprise a self-assembly monolayer of different phosphonic acids of varying length. Therefore, the instant claims are not commensurate in scope.
The declaration states that the coated stents of the instant claims are associated with a 67% reduction in platelet adhesion (p [Symbol font/0x3C] 0.0005), an 84.8% reduction in neutrophil adhesion (p [Symbol font/0x3C] 0.005), and a 67.6% reduction in monocyte adhesion (p [Symbol font/0x3C] 0.001) compared to bare metal stents. The results of this study suggests that the coated stents of the claimed invention perform significantly better than uncoated, bare metal stents. In a highly clinically translatable porcine coronary implant model, the coated stents exhibited 100% patency without any systematic anti-platelet therapy being administered. In comparison, the non-coated stents required systemic daily oral anti platelet therapy to maintain stent patency. The comparison of the coated stents of the instant claims to that of uncoated, bare metal stents is not a comparison of the closest prior art.
Claim Objections
Claim 37 is objected to because of the following informalities: the instant claim 37 comprises the recitation of “ticagrelorcovalently” that is understood to be an error. Appropriate correction is required.
New Grounds of Rejection
Applicant’s arguments, see REMARKS, filed 4/27/26, with respect to the rejection(s) of claim(s) 1,2,4,6,9,16-19 and 37 under 35 U.S.C. 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Kaufmann et al. (J. Biomed. Mater. Res. B: Applied Biomater. Aug 2011 VOL 98B, Issue 2, p280-289), Agrawal et al. (US 2009/0123516A1), Schwartz et al. (US 2006/0194008A1), and Han et al. (US 2017/0087280A1).
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.
Claim(s) 1,2,4,6,9,16-19 and 37 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kaufmann et al. (J. Biomed. Mater. Res. B: Applied Biomater. Aug 2011 VOL 98B, Issue 2, p280-289) in view of Agrawal et al. (US 2009/0123516A1) and Schwartz et al. (US 2006/0194008A1) and in further view of Han et al. (US 2017/0087280A1).
Kaufmann et al. (J. Biomed. Mater. Res. B: Applied Biomater. Aug 2011 VOL 98B, Issue 2, p280-289) discloses drug delivery coronary stents comprising cobalt chromium (CoCr) alloy comprising a metal oxide surface covalently linked to a phosphonic acid self-assembled monolayer (SAM) (abstract; p280, right column, second paragraph; p281, left column, second paragraph).
The cobalt chromium (CoCr) encompasses the cobalt chromium (CoCr) body of the implantable device of the instant claim 6.
The coronary stent encompasses a device configured to be blood contacting of the instant claim 2.
The phosphonic acids comprises dodecylphosphonic acid and phosphonoundecanoic acid (p281, left column, third paragraph).
The phosphonic acid SAM is well-ordered and uniform and comprises a combination of methyl (-CH3) and carboxylic acid (-COOH) terminated phosphonic acids, such as (abstract; p288, Conclusions).
The methyl (-CH3) terminated phosphonic acids encompass the tail portion that are non-reactive with a therapeutic agent of the instant claim 17.
Therapeutic drugs are attached to SAMs via a reactive functional group (p287, left column, last
paragraph to top of right column; p288, Conclusions).
Kaufmann et al. does not explicitly disclose that the stent comprises a plurality of interconnected elongated members that are optionally one or more of closed or open cells, helical coils, or radially expandable rings.
Agrawal et al. (US 2009/0123516A1) discloses a medical device comprising one or more self-
assembled monolayer (SAM) molecules attached to the surface of the medical device (abstract; p2, [0021]).
The medical device comprises an implant made of titanium, stainless steel (316L), cobalt, chromium, etc. (p2, [0023]; p3, [0026-0027]; p28, [0109]; p33-34, [0178]).
The SAM includes three parts - a middle portion and two end portions (covalently attached to each end of the middle portion) (p7, [0096]) wherein the two end portions comprise a first functional group and a second functional group (abstract; p3, [0024]). The SAM molecules can be attached to the surface of the device via a phosphonic acid, etc. (p3, [[0032]; p6, [0091-0092]; p7, [0103]).
One or more therapeutic agents, such as everolimus, tacrolimus, etc. are attached to the one or more SAMs (p2, [0023], p4, [0036],[0041]; p37, [0226])
The medical devices include a stent, etc. (p4, [0037]) that are small, expandable device inserted into a narrowed artery that are classified based on their pattern of metal construction (slotted tube, coil, or mesh) (p33, [0170]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of
the claimed invention that the coronary stents of Kaufmann et al. are expandable devices that may be formed of coils, etc. as Agrawal et al. teaches that vascular stents comprising analogous drug-containing phosphonate SAMs comprise small coils that are expandable in a narrowed artery.
Kaufmann et al. dose not explicitly disclose 12-aminododecylphosphonic acid of the instant claim 9.
Agrawal et al. further discloses that the SAM molecules comprise an opposite end portion group, such as amine, etc. (p7, [0103]) including (12-aminododecyl)phosphonic acid (p10, right column).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize 12-aminododecylphosphonic acid comprising a 12 carbon atom chain of Agrawal et al. for the SAMs of Kaufmann et al. as Kaufmann et al. teaches of dodecylphosphonic acid comprising a reactive functional group for derivatization with a therapeutic agent.
Kaufmann et al. dose not disclose the therapeutic agents of the instant claims or at least two different therapeutic molecules covalently bonded to the tail portion of each of the plurality of molecules of the self-assembled monolayer.
Schwartz et al. (US 2006/0194008A1) discloses implantable substrates/devices comprising a native oxide, such as titanium metal, cobalt-chromium, stainless steel, etc. (p4, [0044]; p24, [0175]; p25,
[0186]).
The implantable substrate/devices comprise an oxide surface (p24, [0172-0177]).
The implantable substrate comprises a phosphonate layer, such as organic phosphonic acids (p4, [0047]) comprising an alkylene between about 2 and about 40 carbon atoms (p4, [0048]; p11, [0101]).
The phosphorus-based layer forms self-assembled monolayers (FIG. 5; p1, [0005]; p33, [0231]).
The phosphorus-based layer has a first, inner surface and a second, outer surface. The first,
inner surface comprises organophosphate moieties covalently bonded to the oxide surface of the implantable substrate p3, [0027]; p4, [0051]; p6, [0060]; p24, [0172-0177]). The IR spectra demonstrated ordered phosphonate films in which substantially all the phosphonates were covalently bound by at least on one oxygen to the oxide surface (p37, [0263]).
The second, outer surface exhibits functional groups at a position remote to or omega to the
organophosphate moieties. The functional groups comprise amino groups for further chemical
modification (p3, [0027]; p4, [0051]; p6, [0060]).
The self-assembled monolayers may be derivatized with active agents, such as sirolimus, tacrolimus, fondaparinux, heparin, etc. or combinations thereof (p13, [0120]; p16, [0132]; p20, [0146-0147]) that encompass the sirolimus, tacrolimus and fondaparinux of the instant claims.
The organophosphate moieties of the self-assembled monolayers may also be unfunctionalized where the portion of the molecules remote to the end covalently bonded to the oxide surface has a
terminal group that contains a usually-non-reactive moiety (p23, [0166]).
Agrawal et al. further discloses that one or more therapeutic agents is attached to the one or more self-assembled monolayer molecules (p2, [0023], p4, [0041]; p37, [0226]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to bind one or more therapeutic agents, such as sirolimus, tacrolimus, fondaparinux, heparin, etc. to the reactive phosphonic acid SAMs of Kaufmann et al. as Schwartz et al. teaches of the combination of sirolimus, tacrolimus, fondaparinux, heparin, etc. drugs bound to phosphonic acid SAMs and Agrawal et al. teaches one or more therapeutic agents attached the phosphonic acid SAMs so that the drugs present at the implant interface and provides a level of precision for highly consistent dose delivery of drugs.
Kaufmann et al. does not disclose the ratio of molecules which are reactive with the therapeutic agent and the spacer molecules, which are non-reactive with the therapeutic agent is about 9:1.
Schwartz et al. further discloses that the functionalized self-assembled monolayers and the
unfunctionalized self-assembled monolayers may each comprise a surface functional group density of at least about 5 times, about 10 times, about 25 times, etc. (p23-24, [0168-0170]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to vary the ratio of functionalized self-assembled monolayers reactive with a therapeutic agent and the unfunctionalized self-assembled monolayers that are nonreactive with the therapeutic agent provided in the composition, according to the guidance provided by Schwartz et al., to provide a composition having the desired ratios and concentrations of therapeutic agents attached to the stents for the effective treatment of various conditions via highly consistent dose delivery of drugs. It is noted that “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Kaufmann et al. does not disclose that one of the two different therapeutic molecules is ticagrelor.
Han et al. (US 2017/0087280A1) discloses drug eluting stents made of titanium, stainless steel, cobalt-chromium, etc. (p2, [0017]; p3, [0041]) comprising multiple drugs, such as the antithrombotic agent ticagrelor, prasugrel, heparin, etc.(p2, [0025]; p3, [0037]) for preventing thrombosis and inhibit inflammation (p4, [0054]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of
the claimed invention to substitute the antithrombotic/anti-platelet agents fondaparinux or heparin of
Schwartz et al. for the antithrombotic agent ticagrelor of Han et al. as antithrombotic agents heparin, prasugrel, and ticagrelor are used analogously as antithrombotic agents for the advantage of preventing thrombosis during implantation of the stent for the treatment of cardiovascular disease that are also and analogous use of the coronary stents of Kaufmann et al.
Response to Arguments
Applicants asserts that the coated stents of the instant claims are associated with a 67% reduction in platelet adhesion (p [Symbol font/0x3C] 0.0005), an 84.8% reduction in neutrophil adhesion (p [Symbol font/0x3C] 0.005), and a 67.6% reduction in monocyte adhesion (p [Symbol font/0x3C] 0.001) compared to bare metal stents. The results of this study suggests that the coated stents of the claimed invention perform significantly better than uncoated, bare metal stents. In a highly clinically translatable porcine coronary implant model, the coated stents exhibited 100% patency without any systematic anti-platelet therapy being administered. In comparison, the non-coated stents required systemic daily oral anti platelet therapy to maintain stent patency. The comparison of the coated stents of the instant claims to that of uncoated, bare metal stents is not a comparison of the closest prior art.
Applicant asserts that Schwartz teaches generally, coatings that include phosphorous-based acid moieties (and this which may encompass hundreds, if not thousands, of potential compounds) for uses in any number of disparate devices, with exemplified benefits in bone-based applications and Agrawal discloses hundreds of potential SAM molecules. The combination does not provide any guidance to arrive at the claimed implantable device (including a metal body with an oxide layer, a SAM with a phosphonic acid head portion bonded to the oxide layer, and a specific set of therapeutic agents).
The reference of Schwartz was not used to explicitly teach of a specific device but was used to teach that phosphorous-based acid moieties are bound to implantable substrates/devices comprising a native oxide, such as titanium metal, cobalt-chromium, stainless steel, etc. via an oxide layer to yield SAM monolayers. Therapeutic agents, such as cardiovascular agents are covalently bound to the SAM the advantage of drug delivery.
The reference of Agrawal was used to teach that phosphoric acid moieties are bound to medical devices comprising titanium, stainless steel (316L), cobalt, chromium, etc. via an oxide layer to yield SAM monolayers. Therapeutic agents are covalently bound to the SAM the advantage of drug delivery to treat cardiovascular disease.
The reference of Kaufmann was used to teach of drug delivery coronary stents explicitly comprising cobalt chromium (CoCr) alloy comprising a metal oxide surface covalently linked to a phosphonic acid self-assembled monolayer (SAM), such as dodecylphosphonic acid and phosphonoundecanoic acid. Therapeutic drugs are attached to SAMs via a reactive functional group for drug delivery.
Applicant asserts that Agrawal discloses hundreds of potential therapeutic agents, ranging from anti-cancer agents, hormones, anesthetics, vasodilators, anti-coagulants, anti-inflammatories, anti-coagulants/anti-platelets, antibiotics, antifungals, analgesics, and opiates. Importantly, neither Schwartz nor Agrawal provides supportive outcome or performance data that remotely approaches the data discussed in the Declaration.
The Examiner’s response to the Declaration is stated above.
The reference of Agrawal was not used to teach of hundreds of potential therapeutic agents but was used to teach that phosphoric acid moieties are bound to medical devices comprising titanium, stainless steel (316L), cobalt, chromium, etc. via an oxide layer to yield SAM monolayers.
The SAM monolayers comprise an opposite end portion group, such as amine, etc. including (12-aminododecyl)phosphonic acid to covalently bind therapeutic agents to the SAM for the advantage of drug delivery to treat cardiovascular disease.
The reference of Kaufmann teaches that the phosphonic acid forming the SAM monolayer comprises dodecylphosphonic acid as well as that stated above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize 12-aminododecylphosphonic acid comprising a 12 carbon atom chain of Agrawal et al. for the SAMs of Kaufmann et al. as Kaufmann et al. teaches of dodecylphosphonic acid SAM comprising a reactive functional group for derivatization with a therapeutic agent.
Conclusion
No claims are allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner
should be directed to MELISSA JEAN PERREIRA whose telephone number is (571)272-1354. The examiner can normally be reached M9-3, T9-3, W9-3, Th9-2, F9-2.
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/MELISSA J PERREIRA/Examiner, Art Unit 1618
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