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 .
The examiner invites applicant to schedule an interview to advance prosecution on the merits should any further claim scope amendment issues remain.
Applicant’s response (amendments, arguments) filed with the 2/24/25 RCE is acknowledged. After amendment, claims 1-4 and 7-17 are pending and examined on the merits.
Applicant’s amendments and arguments thereto have overcome the 35 U.S.C. 102 and 112(b) rejections of record. The rejections under 35 U.S.C. 103 (arguments only, no substantive amendments) and double patenting (request for abeyance, no arguments) have been maintained.
Claim Rejections - 35 USC § 103 – Maintained,
Modified Based on Claim Amendments (Including Cancellation Claims 5-6)
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 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 1-4 and 7-17 remain rejected under 35 U.S.C. 103 as being unpatentable over in Green et al. (U.S. Patent Publication No. 2019/0030122) in view of Trudeau et al. (Fenofibric Acid Reduces Fibronectin and Collagen Type IV Overexpression Human Retinal Pigment Epithelial Cells Grown in Conditions Mimicking the Diabetic Milieu: Functional Implications in Retinal Permeability" Investigative Ophthalmology & Visual Science, August 2017, Vol. 52, No. 9, pp 6348-6354) and/or Rhett et al. (Connexin 43 connexon to gap function transition is regulated by zonula occludens -1" Molecular Biology of the Cell, 01 May 2014, Vol 22, No 9, pq 1516-1528).
The above is in line with the U.S. International Authority disposition in the related PCT written opinion over the same subject matter.
Regarding claim 1, Green teaches a method for modulating the effect of high glucose and inflammatory cytokines in a subject (para (0210), to evaluate the action of high glucose and inflammation on cytokine release and connexin 43 expression and localization using an immobalized human retinal pigmented epithelial cell line (ARPE-19). inflammation was induced by exposing cells to a combination of IL- tbeta and TNF-alpha, potent pro-inflammatory cytokines.; [6230], Co-application of both high glucose and cytokines, however, lead to much higher IL-6, sICAM-1, MCP-4 and IL-8 release relative to basal, high glucose only, and cytokines only (p>/=0.00001 for all) (FIG. 13.), comprising administering an effective amount of a hemichannel blocker to said subject (para [0232], To evaluate the role of connexin 43 hemichannels in high glucose and cytokine-mediated pathology, cells were exposed to Peptagon, a well-established blocker of connexin hemichannels. Results show that Peptagon significantly reduced the secretion of IL-6, IL-8, siCAM-1, and MCP-4 (FIG. 3, p < 0.0004 for all.). Green does not specifically teach modulating blood retinal barrier (BRB) integrity. Trudeau teaches that BRS integrity is disrupted in human retinal pigmented epithelial cells exposed to high glucose and inflammatory cytokines (pg 6348, col 2, para 3, the outer BRB, which is formed by RPE cells attached to one another by fight junctions, at so plays an essential role In preventing the accumulation of extracellular fluid in the subretinal space of the retina. Compromised tight junctions in the RPE cell monolayer are known to contribute to the disruption of the outer BRE and to the impairment of neural retinal function.; pg 6340. col 2 to pg 6354, col 1, para 1, The effect of different conditions tested on the permeability of ARPE-1a monolayers is displayed in Figure 3 interestingly, both (HG + IL-1beta) dramatically increased permeability in what appeared to be a synergistic effect; 9g 6351, cal 2, para 1, Immunostaining of tight junction proteins, 210-1 and claudin-1 showed disruption of the cell monolayer induced by HG + IL-1beta and the beneficial effect of 100 uM FA in preventing the disorganization of tight junction proteins and maintaining the integrity of the monolayer.). Given the increased permeability and disrupted tight junction in RPE cells exposed to high glucose and inflammatory cytokines, as taught by Trudeau, it would have been obvious to one of ordinary skill in the art to have determined whether the compromised BRB integrity can be prevented with hemichannel blockers of GREEN, since GREEN teaches that hemichannel blockers prevent the increase in cytokine release in RPE exposed to high glucose and inflammatory cytokines.
Regarding claim 2, Green teaches a method for modulating the effect of high glucose and inflammatory cytokines in a subject (para [02101 to evaluate the action of high glucose and inflammation on cytokine release and connexin 43 expression and localization using an immortalised human retinal pigmented epithelial cell line (ARPE-19). inflammation was induced by exposing cells to a combination of IL- 1beta and TNF-alpha, potent pro-inflammatory cytokines.; [0230}, Co-application of both high glucose and cytokines, however, lead to much higher IL-6, siCAM-1, MCP-1 and IL-8 release relative to basal, high glucose only, arid cytokines only (Fig. 1) comprising administering an effective amount of a hemichannel blocker to said subject (para [0232], To evaluate the role of connexin 43 hemichannels in high glucose and cytokine-mediated pathology, cells were exposed to Peptagon a well-established blocker of connexin hemichannels. Results show that Peptagon significantly reduced the secretion of IL-6, IL-8, sICAM-1, and MCP-1 (FIG. 3, p < 6.0001 for all). Green does not specifically teach modulating retinal pigment epithelial (RPE} integrity. Trudeau teaches that RFE integrity is disrupted in human retinal pigmented epithelial cells exposed to high glucose and inflammatory cytokines (pg 6348, cal 2, para 3, Compromised tight junctions in the RPE cell monolayer are known to contribute te the disruption of the outer BRB and to the impairment of neural retinal function.: pg 6350, cal 2 to py 6351, col 1, para 1, The effect of different conditions tested on the permeability of ARPE-19 monolayers is displayed in Figure 3 ... Interestingly, both (HG + iL-tbeta)} dramatically increased permeability in what appeared to be a synergistic effect.; og 6351, col 2, para 1, Immunostaining of tight Junction proteins, ZO-1 and iclaudin-1 showed disruption of the cell monolayer induced by HG + IL-ibeta and the beneficial effect of 100 uM FA in preventing the i disorganization of tight junction proteins and maintaining the integrity of the monolayer.}. Given the increased permeability and disrupted tight junction in RPE cells exposed to high glucose and inflammatory cytokines, as taught by Trudeau, it would have been obvious ta one of ordinary skill in the art to have determined whether the compromised RPE integrity can be prevented with hemichannel blockers of GREEN, since GREEN teaches that hemichannel blockers prevent the increase in cytokine release in RPE exposed to high glucose and inflammatory cytokines.
Regarding claim 3-4, Green teaches a method for modulating the effect of high glucose and Inflammatory cytokines in a subject (para [0270], to evaluate the action of high glucose and inflammation on cytokine release and connexin 43 expression and localisation using an immortalised human retinal pigmented epithelial cell tine (ARPE-19). Inflammation was induced by exposing cells to a combination of IL- tbeta and TNF-alpha, potent pro-inflammatory cytokines.; [0230], Co-application of both high glucose and cytokines, however, lead to much higher IL-6, siCAM-1, MOP-1 and IL-8 release relative to basal, high glucose only, and cytokines only (FIG. 1), comprising administering an effective amount of a hemichannel blocker to said subject (para [0232], To evaluate the role of connexin 43 hemichannels in high glucose and cytokine-mediated pathology, cells were exposed io Paptagon, a well-established blocker of connexin hemichannels. Results show that Peptagon significantly reduced the secretion of IL-G, IL-8, siCAM-1, and MCP-4 (FIG. 3, p < 0.0001 for ail}.). Green does not specifically teach modulating tight junction integrity. Trudeau teaches that tight junction is disrupted in human retinal pigmented epithelial cells exposed tu high glucose arid inflammatory cytokines (pg 6348, coal 2, para 3, Compromised tight junctions in the RFE cell monolayer are known to contribute to the disruption of the outer BRB and to the impairment of neural retinal function.; pq 6350, col 2 to pq 6351, col 1, para 1, The effect of different conditions tested on the permeability of ARPE-19 monolayers is displayed in Figure 3 ... interestingly, both (HG + I_-ibeta} dramatically increased permeability in what appeared to be a synergistic effect.; pg 6351, col 2, para 7, Immunostaining of tight junction proteins, ZO-1 and claudin-1 showed disruption of the cell monolayer induced by HG + IL-tbeta and the beneficial effect of 100 uM FA in preventing the disorganization of tight junction proteins and maintaining the integrity of the monolayer.) Given the increased permeability and disrupted gap junction in RPE cells exposed to high glucose and inflammatory cytokines, as taught by Trudeau, it would have been obvious to one of ordinary skill in the art to have determined whether the compromised tight junction integrity can be prevented with hemichannel blockers of GREEN, since GREEN teaches that hemichannel blockers prevent the increase in cytokine release in RPE exposed to high glucose and inflammatory cytokines. Regarding claim 4, GREEN teaches a method for modulating the effect of high glucose and inflammatory cytokines in 3 subject (para {0210}, to evaluate the action of high glucose and inflammation on cytokine release and connexin 43 expression and localization using an immortalised human retinal pigmented epithelial cell line (ARPE-19}. Inflammation was induced by exposing cells to a combination of IL- ibeta and TNF-alpha, potent pro-inflammatory cytokines.; [0230], Co-application of both high glucose and cytokines, however, lead to much higher IL-6, siICAM-1, MCP-1 and IL-8 release relative to basal, high glucose only, and cytokines only (FIG. 1).) Comprising administering an effective amount of a hemichannel blocker to said subject (para [0232], To evaluate the role of connexin 43 hemichannel in high glucose and cytokine-mediated pathology, cells were exposed to Peptagan, a well-established blocker of connexin hemichannels. Results show that Peptagon significantly reduced the secretion of IL-6, IL-8, SICAM-1, ard MCOP-4 (FIG. 3). Green does not specifically teach modulating type [V collagen production. Trudeau teaches that increased type [V collagen production in human retinal pigmented epithelial cells exposed te high glucose and inflammatory cytokines (abstract, Retinal pigment epithelial cells (ARPE-19) were cultured for 18 days in normal glucose (5 mM) or HG (25 mM) medium and studied for the effects of FA on fibronectin (FN) and collagen IV (Col. V) expression ... FN and Coll IV expression were significantly increased in RPE cells grown in HG or HG + IL-1beta medium compared with cells grown in normal medium.}. Given the modulation of collagen IV production in RPE cells exposed to high glucose and inflammatory cytokines, as taught by Trudeau, it would have been obvious to one of ordinary skill in the art to have determined whether the collagen IV production can be modulated with hemichannel blockers of SUL, since GREEN leaches that hemichannel blockers prevent the increase in cytokine release in RPE exposed to thigh glucose and inflammatory cytokines.
Regarding claim 7/(1-4), Green and Trudeau teach the method of any of claims 1-4, wherein the hemichannel blocker is a small molecule hemichannel blocker according to Formula | (GREEN, para [0103], the analogue of Formula II the compound carabersat (N-{(3R,4 $}-6- acetyl-3-hydroxy-2,2-dimieth yl-3,4-dihydrochromen-4-yi-4-fluarsbanzamide} or trans-(+ }-6-acetyl-4-(S)}-(4-fluorabenzoylaming)-3,4-dihydro- 2.2-dimethy!-2H-1-benzofblpyran-3R-ol hemihydrate.) (Note, see instant Specification, para [94}}.
Regarding claim 8/(1-4), Green and Trideau teach the method of claim 7/(1-4), wherein the small molecule hemichannel blocker is N- ((38,48)-6-acety1-3-hydroxy-2,2-dimethy 1-3,4-dihydrochramen-4-y1}-3-chiaro-4-fluorobenzamide (Xiflam) (Green, para [0093], the hemichannel blocker Xiflam may be known by the IUPAC name N-{(38,4S}-6-acetyl-3-hydroxy-2,2-dimethy!-3,4-dihydrochramen-4-yl}-3- shlore-4-fluorabenzamide.).
Regarding claim 9/(1-4), Green and Trudeau teach the method of claim 7/(1-4}, wherein the small molecule hemichannel blocker is a Xiflam prodrug (GREEN, para [0097], the small molecule that blocks or ameliorates or inhibits hemichannel opening is a prodrug of Xiflarn or an analogue thereat).
Regarding claim (10-11)(1-4), Green and Trudeau teach the method of any of claims 1-4, wherein the hemichannel blocker is a peptidomimetic connexin 43 hemichannel blocker, Peptides (Green, para [0216], Peptides (H-Val-As-Cys-Phe-Leu-Ser-Arg-Pro-Thr-Giu-L ys -Thr-OH; China Peptides, China).
Regarding claim 12, Green and Trudeau teach the method of claim 1, wherein said hemichannel blocker is administered to achieve a final circulating concentration of the hemichannel blocker ranging from about 10 to about 250 micromolar (Green, para [0169], for example Xiflam, or peptide or peptidomimetic hemichannel blockers, may be administered systemically, such as by intravenous, Intra-arterial or intraperitoneal administration, such that the final circulating concentration is from approximately 0.001 to approximately 150 micromolar.).
Regarding claim 13, Green and Trudeau teach the method of claim 1, wherein said hemichannel blocker is administered by injection (Green, para (0169). for example Xiflam, or peptide or peptidomimetic hemichannel blockers, may be administered systemically, such as by intravenous, intra-arterial or intraperitoneal administration).
Regarding claim 14, Green and Trudeau teach the method of claim 1, wherein said hemichannel blocker is administered orally (Green, para (0194), Xiflam may be administered orally once a day at a dose of approximately 2 mg to approximately 40 mg.}. Regarding claim 15, GREEN and Trudeau teach the method of claim 1, wherein the hemichannel blocker is administered PRN or ona predetermined schedule or both (Green, para [0147], Hemichannel blocker does, alone or together with cytokine antagonist doses (in combined or separate formulations), may be administered QD, BID, TID, QD, or in weekly doses, e.g., QI, BIW OW. They may also be administered PRN (as needed}, and HS (bedtime).
Claims (7-11)/(1-4) are obvious over Green further in view of Rhett
Green is discussed above.
Regarding claim 7/(1-4), Rhett teaches the method of claim 5, but does not specifically teach wherein the hemichannel blocker is a small molecule hemichannel biocker according to Formula 1. Green teaches a hemichannel blocker comprising a small molecule hemichannel blocker according to Formula | (para (0103), the analogue of Formula [is the compound carabersat (N-[(3R,4 S)-8-acetyl-3-hydroxy-2,2- dimethyl-3,4-dih ydrochromen-4-yi}-4-fluorobenzamide) or trans-{+}-G-acelty-4-(S }-(4-fluorobenzoylamine}-3,4-dihydro-2,2-dimethy-2H-t- benzo[bjpyran-3R-ol hemihydrate.) (Note, see instant Specification, para [91]). Given that said hemichannel blocker is known to a skilled artisan, it would have been obvious to one of ordinary skill in the art to have applied said hemichannel blocker, as taught by GREEN to determine whether the changes in the gap junction, as taught by Rhett, can be confirmed by a known hemichannel blocker.
Regarding claim 8/(7, 1-4), Rhett and Green teach the method of claim 7/1-4, wherein the small molecule hemichannel blocker is N-[(35,48}-6- acety1-3-hydroxy-2,2-dimethy 1-3.4-dihydrachromen-4-y1}-3-chlore-4-fluorobenzamide (Xiflam) (Green, para (G093], the hemichannel blocker Xiflam may be known by the IUPAC name N-[(35,43}-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yi}-S-chiaro-4- fluorobenzamide.)}
Regarding claim 9/(1-4), Rhett and Green teach the method of claim 7/1-4, wherein the small molecule hemichannel blocker is a Xiflam prodrug (Green, para [0097}, the small molecule that blocks or ameliorates or inhibits hemichannel opening is a prodrug of Xiflam or an analogue thereof.).
Regarding claims (10-11), Rhett does not specifically teach wherein the hemichannel blocker is a peptidomimetic connexin 43 hemichannel blocker.. Green teaches a hemichannel blocker peptidomimetic comprising peptides (para [0218], Peptides (H-Val-As-Cys-Phe-Leu-Ser-Arg-Pro-Thr-Giu-Lys-Thr-OH; China Peptides, China) was administered to cells challenged with high glucose and pro-inflammatory cytokines.). Given that the efficacy of said hemichannel blocker peptides (Green, para [0216], These concentrations have been shown to black connexin 43 hemichannels with minimal effect on gap junction cell-cell coupling) is known to a skilled artisan, it would have been obvious to one of ordinary skill in the art to have applied said hemichannel blocker, peptides, as taught by Green to determine whether the changes in the gap junction, as taught by Rhett, can be confirmed by a known hemichannel blocker.
Response to Arguments (No Substantive Amendments)
Applicant’s arguments (no substantive amendments) have been fully considered but are not yet found persuasive. The examiner is open to further interview to advance prosecution on the merits. Regarding the arguments over the prior art combination of Green and Trudeau and/or Rhett, the following is conveyed, starting with the final argument as to secondary considerations of unexpected results (page 11 response):
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The asserted surprising/unexpected findings above, without more, are deemed naturally occurring and expected receptor binding effects as to connexin hemichannels and RPE/BRB. Alone, these natural/expected receptor binding asserted surprising/unexpected do provide something unexpected over that which the prior art combination is maintained as rendering the instantly claimed invention prima facie obvious.
As no substantive amendments have been carried out, the following are conveyed, in line with that previously of record:
In response to applicant's primary argument that the prior art did not appreciate that certain tissue integrity could be modified by hemichannel blockers, the fact that applicant 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. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
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).
In response to applicant's further arguments, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Lastly, in response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
Thus, the prior art combination is maintained as rendering the instantly elected and now claimed invention prima facie obvious for the rationale and reasons of record.
Double Patenting – Maintained, No Response, Request for Abeyance
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-4 and 6-17 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-75 of U.S. Patent No. 10465188. Although the claims at issue are not identical, they are not patentably distinct from each other because ‘188 claims the treatment of “retinal perfusion injury” which would constitute an umbrella class over the instantly claimed 1 and 2 modulating BRB integrity and RPE integrity, respectively, where treatment of the former would equally treat the latter. Further, ‘188 expressly teach treating such with connexin hemichannel blockers as instantly claimed and the other elements of administration here.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAURY AUDET whose telephone number is (571)272-0960. The examiner can normally be reached on M-Th. 7AM-5:30PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Alstrum-Acevedo can be reached on 571-272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MAURY A AUDET/Primary Examiner, Art Unit 1654
