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 .
Claim Status
Claims 65-67 are new.
Claims 1-43, 59, 63 and 64 are cancelled.
Claims 44-58, 60-62 and 65-67 are pending.
Claims 45-47 and 60-64 are withdrawn.
Claims 44, 48-58 and 65-67 are under examination. Applicant’s amendment has necessitated new ground of rejection. Accordingly, this Action is FINAL.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/4/25 was filed after the mailing date of the non-FINAL Action on 10/10/25. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn rejections
Applicant's amendments and arguments filed 2/10/26 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or objection not specifically addressed below is herein withdrawn.
Claims 44 and 48-58 were rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph; Claim 49 was rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph; Claims 50, 52, 53, 54 and 56 were rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph; and Claims 50 and 54 were rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. Applicant has amended to the claims to overcome these rejections.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 44, 48-58 and 65-67 are rejected under 35 U.S.C. 103 as being unpatentable over Weber et al. (US20070244569) and Oscarson et al. (WO2010029189) and Martins et al. (Colloid Polym Sci 2011;289:1133-1144).
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103, the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103.
Applicant claims, for example:
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Level of Ordinary Skill in the Art
(MPEP 2141.03)
MPEP 2141.03 (I) states: “The “hypothetical ‘person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988). The level of skill is that of a biocompatible medical device/materials research scientist, as is the case here, then one can assume comfortably that such an educated artisan will participate in clinical research to contribute to the field and stay current with the latest advancements in medical devices/materials, such as endovascular devices, and techniques, including biomedical engineers specializing in medical device design focused on the development, manufacturing, and regulatory aspects of biocompatible implants/endoprosthetics, have knowledge of the materials used in medical devices, such as metal alloys, plastics, and fabrics, and their interaction with the human body.
In addition, the prior art itself reflects an appropriate level (MPEP 2141.03(II)).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Regarding claims 44, 48, 51, 52 and 56-58, Weber et al. is directed to a medical device for implantation into an organism (Claims 1 and 38), comprising underlying structure having a fiber meshwork (Claim 1) that appears non-woven (Figures 1A and 2) made of a polymer (Claim 13) and further comprising a layer-by-layer (LbL) coating on the fiber meshwork wherein the layer-by-layer coating comprises a first layer of a first polyelectrolyte, and a second layer of a second polyelectrolyte (Claims 27-28) selected from cationic polyallylamine hydrochloride (PAH) and polycation chitosan [0087-0088, 0133] as well as anionic heparin [0101, 0124, 0169, 0171] and anionic polystyrene sulfonate (PSS) [0133], which creates a material biocompatible with blood. Thus, combinations of anionic heparin and cationic chitosan and anionic PSS and cationic PAH alternating layer pairs with the PAH/PSS as an outer layer pair implicitly serving as a substrate for end-point functionalization of heparin are readily envisaged by the ordinary artisan. Weber et al. teach arranging the layers in any combination of layers [0130], which reasonably reads on mixtures of the coating components.
Regarding claims 44, 48 and 49, Weber et al. teach in other unclaimed embodiments, where the polymer can be expanded PTFE [0162], which is the elected species, such that the non-woven fibers would then consist of the ePTFE.
Regarding claim 50, Weber et al. teach that the fibers have a diameter of <1 micron(Claim 21), which overlaps the claimed range of about 0.1-10 microns. See MPEP 2144.05(I): In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).
Regarding claim 54, Weber et al. suggest an embodiment with a layer that may exhibit better adhesion of the surface of the tubular structure [0109], thus providing an adhesion agent to the material.
Regarding claims 55-58, Weber et al. teach: “The number of layers and/or the total thickness of a multi-layered structure deposited on a fiber meshwork, or an underlying structure, can be determined empirically and can be a function of, for example, the compositions of the layers and the type of medical device. For example, for a given medical device, the number of layers, their sequences and compositions, and/or the total thickness of multi-layered structure can be varied and the effectiveness of the multilayered structure can be tested.” [0122]. Thus, the number of layers is subject to routine optimization. Weber et al. also teach that the number of layers varies by according to application and in some embodiments can be at least 10 layers [0120] and suggests from 5 to 50 layers [0126] or can be coated with just 1 layer [0111], which creates a range of layers from 1-10 and overlaps the claimed 3-8 layer pairs and 4 pairs of claim 58.
Regarding claim 67, Weber et al. teach: “once a layer having a preselected charge is provided on the underlying structure or fiber meshwork, the layer can be coated with a layer of an oppositely charged material.” [0116] Weber et al. teach PAH as a polyelectrolyte cation [0088, 0105-0106] and PEI [0133] where Weber et al. teach PEI to “facilitate deposition of a first layer of a layer-by-layer structure upon it.” [0119]. Thus, Weber et al. render obvious first coating the biocompatible non-woven fibers with a pre-coating deposit comprising an adhesion agent as claimed.
Regarding claims 44, 53, 57-58 and 66, Oscarson et al. teach non-thrombogenic medical devices with end-point attached heparin (Claims 2-3 and 25), to prevent coagulation or thrombus formation (Claim 1) wherein the surface comprises one or more coating bilayers of cationic polymer and anionic polymer, the innermost layer being a layer of cationic polymer and the outermost layer being a layer of cationic polymer covalently attached to the entity (Claim 7) and where the device can be a stent (Page 11, lines 4-9). Oscarson et al. teach: “The advantage of end point attachment, especially reducing end point attachment, is that it is expected that the biological activity of the heparin moiety is maximized due to enhanced availability of the thrombin interaction sites as compared with attachment elsewhere in the heparin moiety.” (Page 4, line 36 through page 37, line 4). The coating with end point conjugation of heparin naturally attracts endothelial cells.
Regarding claims 44, 52 and 65, Martins et al. teach N,N,N-trimethyl chitosan (TMC) treated with heparin to form a polyelectrolyte complex (Title; abstract) where the TMC maintains or surpasses chitosan (CHT) properties such as biodegradability and higher solubility and permeation in basic and neutral media (Page 1134, left column 1st paragraph).
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02) and Finding of prima facie obviousness
Rational and Motivation (MPEP 2142-2143)
1. The difference between the instant application and Weber et al. is that Weber et al. do not expressly teach a heparinized multilayer polymer coating with end-point heparin functionalization wherein the last LbL layer of (Hep/Chi)5 or (PSS/PAH)4 is functionalized with heparin by end-point conjugation and wherein the chitosan analogue is a N-alkylated chitosan, in particular tri-methyl chitosan. This deficiency in Weber et al. is cured by the teachings of Oscarson et al. and Martins et al.
1. It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the blood compatible material of Weber et al. by heparinizing the multilayer polymer coating with end-point heparin functionalization wherein the last LbL layer of (Hep/Chi)5 or (PSS/PAH)4 is functionalized with heparin by end-point conjugation, as suggested by Oscarson et al., and wherein the chitosan analogue is a N-alkylated chitosan, in particular tri-methyl chitosan, as suggested by Martins et al., and produce the instant invention.
One of ordinary skill in the art would have been motivated to do this because Oscarson et al. teach: “The advantage of end point attachment, especially reducing end point attachment, is that it is expected that the biological activity of the heparin moiety is maximized due to enhanced availability of the thrombin interaction sites as compared with attachment elsewhere in the heparin moiety.” Since it is desirable to maximize the biological activity of heparin, the ordinary artisan is strongly motivated to end-point conjugate the heparin to the anion-cation bilayers for that advantage with a reasonable expectation of success. Whether the anion-cation bilayer is (Hep/Chi)5 or (PSS/PAH)4 with an optional adhesion agent is at the discretion of the ordinary artisan and subject to routine optimization as taught by Weber et al. Also note that optional components are not required. The MPEP provides, “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure.” See MPEP § 2111.04. Regarding the tri-methyl chitosan limitation, the ordinary artisan is motivated to employ tri-methyl chitosan for not only the superior properties over chitosan as taught by Martins et al. but also the same functional ability to form polyelectrolyte complexes with heparin. “Where two known alternatives are interchangeable for a desired function, an express suggestion to substitute one for the other is not needed to render a substitution obvious." In re Fout 675 F.2d 297, 301 (CCPA 1982). The ordinary artisan would do so with a reasonable expectation of success.
The difference between the instant application and Weber et al., as modified by Oscarson et al. and Martins et al., is that Weber et al., as modified by Oscarson et al. and Martins et al., do not expressly teach wherein the biocompatible non-woven fibers are first coated with a pre-coating deposit comprising an adhesion agent for the multilayer polymer coating such as a cationic polymer, in particular poly( ethylene imine) (PEI) or poly(allyl amine hydrochloride) (PAH). However, Weber et al. teach and suggest pretreating an underlying structure for LbL deposition [0130] and suggest providing a positive charge with an amine or imine or other basic groups [0131] such as polyallylamine or polyethyleneimine [0133] where PAH is taught [0088]. It then requires no inventive effort to first coat the fibers with a pre-coating deposit comprising an adhesion agent of PEI or PAH for the layer-by-layer deposition with a reasonable expectation of success.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. 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 combined references, especially in the absence of evidence to the contrary.
Response to Arguments:
Applicant’s arguments filed on 2/210/26 have been carefully considered but are not persuasive.
On pages 10-11 of remarks, Applicant asserts that: “There is no specific suggestion of combination of heparin and PSS layers nor of PSS/PAH layers according to the present invention. Further, Weber et al. fail to provide any data regarding
LBL coatings composed of alternating layers of PSS or PAH (negatively charged) and HPSA or PDMAEMA or PAH (positively charged) nor does the reference teach or suggest that the polyelectrolytes should be covalently bonded to an underlying layer.” Respectfully the Examiner has a different perspective. The test for obviousness is "what the combined teachings of the references would have suggested to those of ordinary skill in the art." In re Keller, 642 F.2d 4I3, 425 (CCPA I98I) (MPEP 2145(III)). In the present case, the reference of Weber et al. teaches and suggests layer-by-layer coating wherein the anionic polymer is selected from heparin and poly(sodium 4-styrene sulfonate) (PSS) or a mixture thereof and the cationic polymer is selected from chitosan or an analogue thereof and poly(allyl amine hydrochloride) (PAH) or a mixture thereof. The combined references render obvious end-point functionalization with heparin as well as employing N-alkylated chitosan for the desirable benefits provided. There is no requirement that Weber et al. reduce to practice every embodiment within the scope of Weber et al.’s invention nor is Weber et al. required to run experimental data on every embodiment. The fact of the matter is that Weber et al. teach and suggest a material compatible with blood comprising biocompatible non-woven fibers of a multi-layer polymer layer-by-layer coating as claimed and the secondary references suggest the benefits of end-point functionalization with heparin and employing a chitosan analogue as claimed. Applicant asserts: “there is no teaching that suggests covalently bonding/attaching the polyelectrolyte layer to the underlying layers.” However, claim 44 does not require covalent bonding/attaching the polyelectrolyte layer to the underlying layers. Applicant argues: “there is absolutely no teaching in Weber et al. regarding the selection of the layer pairs and that heparin would need to be coated on-to the outer layer pair by end-point attachment.” However, Weber et al. do teach and suggest the claimed layer pairs and the secondary reference teaches end-point attachment. Applicant’s argument is not persuasive.
On page 11 of remarks, Applicant comments on Oscarson et al. and notes that Oscarson et al. do not describe the surface onto which the LBL coating is applied comprises no-woven fibers and that Oscarson et al. fail to teach or suggest that the cationic polymer is chitosan or PAH, and that the anionic polymer is heparin or PSS.
Oscarson et al. also do not suggest that the cationic polymer could be chitosan or PAH and the anionic polymer could be heparin or PSS. However, Oscarson et al. is relied upon as cited in the rejection and Weber et al. teach and suggest the cationic polymer and the anionic polymer as claimed. It is impermissible to attack references singly when the Examiner relies upon the combined teachings of the references, nor may they attack a reference for not teaching a limitation of the claim when the Examiner has explicitly relied upon another reference as teaching that limitation. See In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000). Applicant’s argument is not persuasive.
On pages 11-12, Applicant asserts that Martins et al. studied the release of heparin from bulk polyelectrolyte complexes and that bulk systems cannot directly be compared to thin films on surfaces since many dynamic and volume-associated aspects in bulk are very different from the ones in ultra-thin coatings. However, that is not the focus of the rejection and as asserted above, the ordinary artisan is motivated to employ tri-methyl chitosan for not only the superior properties over chitosan as taught by Martins et al. but also the same functional ability to form polyelectrolyte complexes with heparin. “Where two known alternatives are interchangeable for a desired function, an express suggestion to substitute one for the other is not needed to render a substitution obvious." In re Fout 675 F.2d 297, 301 (CCPA 1982). The trimethyl chitosan is a superior alternative for the same desired function and thus an obvious choice by the ordinary artisan in this art. Applicant’s argument is not persuasive.
On pages 12-13 of remarks, Applicant asserts that the invention has superior property of sustained inhibition of thrombin in human plasma for up to 5 or 7 days compared to the controls and adherence of endothelial cells to the multilayer polymer LbL coating. Respectfully, the Examiner has a different perspective. The data for Figure 4 was derived from the Antithrombotic properties study (Page 24) which states: “the amount of anticoagulant that was released from the graft when incubated with human plasma was evaluated.” Control examples C1 and C6 did not have any heparin present and as noted by Applicant, will show no anti-Xa increase (Specification page 24, line 31). Control examples 2-5 all contains dextran sulfate (DS). It is well known in the art that dextran sulfate forms strong complexes with chitosan that can be irreversible (See Delair, T. European Journal of Pharmaceutics and Biopharmaceutics 2011;78:10-18; “the presence of the sulfate groups ensures strong electrostatic interactions with the ammonium groups of chitosan” (Page 10, bottom right column); and: “when the charge ratio reached unity, the system irreversibly aggregated” (Page 12, right column 2.4.)). So, the lack of anticoagulant release may be due to the selection of such a strong interaction that prevents anticoagulant release. Additionally, Weber et al. do not teach or suggest dextran sulfate for the anionic polyelectrolyte. Consequently, the comparison presented by Applicant is not against the closest prior art. Figure 4c shows no thrombin generation inhibition for the control examples C1 and C6 while inventive examples with heparin do. That appears to be an expected result. Control examples with end point heparin were not tested in 4b or 4c. So, the conclusions drawn by Applicant appear skewed. Applicant asserts that Example 2c demonstrates adherence of endothelial cells to the LbL coating which is shown in Figure 6 with the gray represent smooth muscle cells and the black representing endothelial cells:
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Respectfully, the Examiner can discern no significant difference between the inventive examples and the control examples. Applicant’s argument is not persuasive.
In conclusion, MPEP 2141 III states: “The proper analysis is whether the claimed invention would have been obvious to one of ordinary skill in the art after consideration of all the facts.” Respectfully, after review of all the facts, Applicant’s arguments are not persuasive. The Examiner has reached a determination that the instant claims are not patentable in view of the preponderance of evidence and consideration of all the facts, which is more convincing than the evidence which has been offered in opposition to it.
Conclusion
No claims are allowed.
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 ERNST V ARNOLD whose telephone number is (571)272-8509. The examiner can normally be reached M-F 7-3:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Brian Y Kwon can be reached at 571-272-0581. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ERNST V ARNOLD/Primary Examiner, Art Unit 1613