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 .
Applicant’s 6-2-26 election of the species of invention which involves the use of an anti-AGE antibody is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-3, 7, 8, 11-25 are pending.
Claims 1-3 and 11-25 are under examination as they read on “the species of method which employs an anti-AGE antibody.”
Claims 7 and 8 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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 6-2-23.
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) 1-3, 12 and 14-25 are rejected under 35 U.S.C. 103 as being unpatentable over Nonaka et al. (J Periodontal Res. 2018 Jun;53(3):334-344, cited herewith) in view of Gruber et al. (20160215043), cited herewith) as evidenced by Loesche et al. (Clinical Microbiology Reviews, Oct. 2001, p. 727–752, cited herewith).
As a preliminary matter, note that periodontitis has long been known to be the result of chronic bacterial infection in the gum tissue (gingival tissue) of the oral cavity (see Loesche, e.g., at page 745-46 bridging paragraph). Likewise, as further taught by Loesche at page 727-28 bridging paragraph, “The prevalence of periodontal disease increases with age (36, 87, 88, 145, 217, 219) and as more people are living longer and retaining more teeth, the number of people developing
periodontal disease will increase in the next decades.”
The teachings of Nonaka in view of Guber as evidenced by Loesche
At the second paragraph of their Introduction, Nonaka teaches AGEs accumulate in periodontal tissues in greater amounts in patients with DM than in individuals without DM13 and are present in epithelial cells, fibroblasts, endothelial cells and inflammatory cells in the periodontal tissues of patients with DM.14 RAGE is also known to be expressed in the gingival tissues of patients with DM,15 and RAGE mRNA expression in human gingival fibroblasts (HGFs) was previously shown to be increased by AGEs.16 AGEs inhibit collagen synthesis in HGFs,17 increase the expression of matrix metalloproteinase 1 (MMP-1) in HGFs,18 and decrease alkaline phosphatase activity and osteocalcin expression, but increase IL-1β expression in rat osteoblastic cells.19 These findings suggest that AGEs aggravate inflammation, the destruction of periodontal tissues and bone resorption in DM-associated periodontitis.”
Moreover, the final paragraph of the Discussion section of Nonaka further teaches “AGEs bind to RAGE on endothelial cells, epithelial cells and fibroblasts in periodontal tissues,15,16 and RAGE is strongly expressed in the gingiva of patients with DM and periodontitis,47… These
findings and our results suggest that AGEs influence DM complications via the RAGE, MAPK and NF-κB pathways. Therefore, AGEs aggravate inflammatory responses by upregulating IL-6
and ICAM-1 expression via the RAGE, MAPK and NF-κB pathways in gingival fibroblasts and influence the pathogenesis of DM-associated periodontitis. The blockade of this AGE signaling pathway has potential in the treatment of DM-associated periodontitis.”
However, Nonaka does teach the treatment of the periodontitis infection by administering an anti-AGE antibody, or the various elements of dependent claims 2, 3 and 11-25.
At para 5, Gruber teaches an “…Advanced glycation end-products (AGEs; also referred to AGE-modified proteins, or glycation end-products) arise from a non-enzymatic reaction of sugars with protein side-chains in aging cells…[t]his process begins with a reversible reaction between the reducing sugar and the amino group to form a Schiff base, which proceeds to form a covalently-bonded Amadori rearrangement product. Once formed, the Amadori product undergoes further rearrangement to produce AGEs. Hyperglycemia, caused by diabetes mellitus (DM), and oxidative stress promote this post-translational modification of membrane proteins….AGEs have been associated with several pathological conditions including diabetic complications, inflammation….” (emphasis added).
At paras 33-34, Gruber further teaches the production of anti-AGE antibodies that bind to “…AGE-modified proteins having an AGE modification such as FFI, pyrraline, AFGP, ALI, carboxymethyllysine, carboxyethyllysine…,” noting that in some instances Gruber refers to “carboxymethyllysine” as “carboxymethyl lysine” / “CML.” Gruber describes the production of pharmaceutical compositions comprising said anti-AGE antibodies and a pharmaceutically acceptable carrier for intravenous administration of said anti-AGE antibodies (see paras 57-58), including formatting the antibody in a “unit dosage form” to “facilitate administration and dosage uniformity” (see para 62), and reference claims 10 and 11 describe a method of treatment with an anti-AGE atnbiody wherein the antibody is administered in either a unit dosage or a multidosage form. At para 33 Gruber teaches their anti-AGE antibody “…is non-immunogenic to the animal in which it will be used, such as non-immunogenic to humans; companion animals including cats, dogs and horses; and commercially important animals, such camels (or alpaca), cattle (bovine), sheep, and goats,” consistent with the requirement of instant claim 17.
Finally, claims 12-14 of Gruber recite the following:
“12. A method of treating a subject with sarcopenia, comprising administering a composition comprising a first anti-AGE antibody and a second anti-AGE antibody; wherein the second anti-AGE antibody is different from the first anti-AGE antibody.
13. The method of claim 12, wherein the first anti-AGE antibody and the second anti-AGE antibody bind AGE antigens comprises at least one protein or peptide that exhibit
different AGE modifications selected from the group consisting of FFI, pyrraline, AFGP, ALI, carboxymethyllysine, carboxyethyllysine and pentosidine.
14. The method of claim 12, wherein the first anti-AGE antibody binds a carboxymethyllysine-modified protein,” and
claim 15 of Gruber recites “[a] method of treating sarcopenia, comprising administering
to a subject a composition comprising an anti-AGE antibody, said method further comprising:
testing the subject for effectiveness of the administering at treating the sarcopenia; followed by
a second administering of the anti-AGE antibody.”
Given the reference teachings it would have been obvious to one of ordinary skill in the art to treat DM-associated periodontitis as a consequence of chronic periodontal infection in humans by administering an anti-AGE antibody, such one or more anti-AGE antibodies described by Gruber, so as to blocks the binding of AGE-modified proteins to RAGE (Receptor for Advanced Glycation End-Products)(see Gruber at paras 5 and 34). It would have been obvious to one of ordinary skill in the art to attempt to neutralize the AGE-modified proteins that form as a consequence of diabetes mellitus (DM), and which increase the expression of inflammation-related factors such as IL-6 in the context of human gingival fibroblasts (HGFs) and periodontitis associated with bacterial infection, by administering an anti-AGE antibody as described by Gruber since these antibodies would be reasonably expected to block or inhibit the ability of AGE-modified proteins to interact with RAGE.
Various reasons the ordinarily skilled artisan would have been motivated to block AGE-induced RAGE signaling were known from the prior art teachings of Nonaka set forth above; moreover, additional mechanisms by which the effects of AGE-modified proteins contribute to the pathogenesis of periodontitis are set forth at Nonaka, 1st and 2nd paras (emphasis added):
“AGEs induce increases in inflammation and upregulation of tissue degradation in patients with DM resulting in end-organ complications such as microvascular diseases, nephropathy, neuropathy and retinopathy. AGEs increase the expression of proinflammatory cytokines
such as IL-1β, IL-6 and tumor necrosis factor-α in some tissues and inhibit collagen synthesis in gingival fibroblasts… AGEs and the pathogens of periodontitis are considered to aggravate
inflammation and degrade periodontal tissues in patients with periodontitis and DM.”
“…In the present study, AGEs increased IL-6 expression in HGFs and promoted the production of IL-6 and ROS activity in combination with P.g-LPS (data not shown). In addition, the combination of AGEs and P.g-LPS [“Porphyromonas gingivalis lipopolysaccharide”] further increased the expression of inflammation-related factors and inhibited the differentiation of osteoblastic cells.19 These findings suggest that high glucose concentrations and AGEs
induce inflammation in periodontal tissues by upregulating IL-1β, IL-6 and IL-8 expression in DM, and the combination of P.g-LPS, hyperglycemia and AGEs may induce severe DM-associated periodontitis.”
As to the methods of treatment comprising administering first and second anti-AGE antibodies that each independently bind AGE antigens comprising at least one protein or peptide that exhibit different AGE modifications selected from the group consisting of FFI, pyrraline, AFGP, ALI, carboxymethyllysine, carboxyethyllysine and pentosidine as encompassed in the breadth of claims 1, 2, 3 and 23, given the teachings of Gruber it would have been obvious to one of ordinary skill in the art that various anti-AGE antibodies binding different advanced glycation modifications should be used in any therapeutic method of treatment since a wide variety of structurally distinct AGE-modified proteins will necessarily occur when the sugars of various glycated proteins react with protein side chains (see Gruber at para 17).
Furthermore, as to practicing a step of “testing the subject for effectiveness of the first administration at treating the infection” prior to administering said second anti-AGE antibody as recited in claim 3, it further would have been obvious to do so given that claim 15 of Gruber is drawn to a therapeutic method employing this same strategy.
Finally, as to the “local administration” limitation of claim 19, given the teachings of Nonaka it likewise would have been obvious to one of ordinary skill in the art to locally administer the anti-AGE antibody or antibodies of Gruber directly into the sulcus / periodontal pocket since this was the location where the infection associated with periodontitis was known to occur (see Loesche at page 730, right col., last full paragraph – col. bridging paragraph).
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 1, 3, 12, 15-17, 20-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. (11518801, cited herewith) as evidenced by Loesche et al. (Clinical Microbiology Reviews, Oct. 2001, p. 727–752, cited herewith).
Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims drawn to a method of treating diabetes or diabetic complications, comprising killing senescent cells by administering to a subject a composition comprising an anti-AGE antibody, wherein the diabetic complication comprises at least one disease or disorder selected from… periodontal disease… anticipate the instant claims. Note in this regard that as described by the teachings of Loesche set forth above, periodontitis has long been known to be the result of chronic bacterial infection in the gum tissue (gingival tissue) of the oral cavity.
No claims are allowed. However, claims 11 and 13 are objected to as being dependent upo a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY S SKELDING whose telephone number is (571)272-9033. The examiner can normally be reached M-F 9-5 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644
Prosecution Insights