DETAILED ACTION
Status of the Claims
Claims 1-3, 5-16, 18, and 20-28 are pending in the instant application. Claims 12-16, 18, 20 and 21 have been withdrawn based upon Restriction/Election as discussed below. Claims 1-3, 5-11 and 22-28 are being examined on the merits in the instant application.
Request for Continued Examination
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01/12/2026 has been entered.
Advisory Notice
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.
Priority
The U.S. effective filing date has been determined to be 05/16/2019, the filing date of the GB1909617.8 (Applicant's foreign priority document).
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 1-3, 5-11 and 22-28 remain rejected under 35 U.S.C. 103 as being unpatentable over VARUM (US 2016/0250232; published September, 2016) in view of Guiotto et al. (“Carnosine and Carnosine-related Antioxidants: A Review,” 2005, Bentham Science Publishers Ltd.; Current Medicinal Chemistry, Vol. 12, pp. 2293-2315); PRAVDA (US 2010/0184728; published July, 2010); HESLET (WO 2016/012608 A1; published January, 2016); and MOLLER (US 2007/0031374; published February, 2007), and MADSEN (US 2011/0105720; published May, 2011).
Applicants Claims
Applicant claims a pharmaceutical composition comprising an active ingredient comprising an antibody or fragment thereof, carnosine, and diglycine; wherein the carnosine and diglycine stabilize the active ingredient in the lower gastrointestinal tract of a subject (instant claim 1). Applicant further claims the dosage form is solid or semi-solid for oral administration (claim 5) having an enteric coating (claim 6), the solid dosage form including a core and a coating thereon, the core comprising the active ingredient, the coating comprising a mixture of a digestible polysaccharide and a film-forming material which has a solubility threshold at pH 6.0 or above (claim 7). Applicant claims the digestible polysaccharide is selected from the group consisting of starch, amylose, amylopectin, chitosan, chondroitin sulfate, cyclodextrin, dextran, pullan, carrageenan, scleroglucan, chitin, curdlan and levan (claim 8). Applicant claims the film-forming material is an acrylate polymer, a cellulose polymer or a polyvinyl-based polymer (claim 9).
Applicant claims an orally administrable pharmaceutical composition comprising an active ingredient comprising an antibody or fragment thereof, carnosine, and diglycine, wherein the carnosine and diglycine stabilize the active ingredient in the lower gastrointestinal tract of a subject (instant claim 10).
Applicant claims a solid dosage form for oral administration comprising: a core comprising: an active ingredient comprising an antibody or fragment thereof, carnosine, diglycine; and a delayed release coating for the core, wherein the carnosine and diglycine stabilize the active ingredient in the lower gastrointestinal tract of a subject (instant claim 11).
The instant Specification discloses that: “Suitable antibodies for use in the invention include adalimumab, infliximab, ruplizumab, cetrolizumab pegol, golimumab, natalizumab, vedolizumab, tildrakizumab, ustekinumab and combinations thereof.” (p. 6, lines 15-17). And further that: “The one or more di-peptides and optionally the enzyme inhibitor cause at least 5% of the protein present to remain intact after 4 hours in the gastrointestinal fluid. Preferably at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90% 95% or more of the protein remains intact.” (p. 7, lines 8-11). The instant Specification does not define the claim term “stabilize” and is therefore being interpreted as any measurable improvement in stability of the “antibody or fragment thereof”.
Elected Species: Applicants have elected the following species in the reply filed 03/10/2025: (a)(i) a protein is an antibody, (a)(ii) one or more dipeptides is carnosine, (a)(iii) enzyme inhibitor is aprotinin; (b)(i) dosage formulation is solid, and (b)(ii) administration form is oral.
Determination of the scope
and content of the prior art (MPEP 2141.01)
VARUM teaches a delayed release drug formulation “comprising a core containing a drug and a delayed release coating for providing intestinal release, release of the drug in the colon is accelerated by including an isolation layer between the core and the delayed release coating. The delayed release coating comprises an inner layer and an outer layer. The outer layer comprises a pH dependently soluble polymeric material which has a pH threshold at about pH 5 or above.” (title, abstract, see whole document). VARUM taches that: “Release of drugs in the colon typically requires an alternative approach. The colon is susceptible to a number of disease states, including inflammatory bowel disease, irritable bowel syndrome […]. In such conditions, drug targeting to the colon would maximise the therapeutic effectiveness of the treatment. The colon can also be utilised as a portal for the entry of drugs into the systemic circulation. Various formulations have been developed for colonic drug delivery, including pro-drugs as well as formulated dosage forms, with the latter being more popular since the concept once proved can be applied to other drugs.” ([0005]).
VARUM teaches their dosage form “delayed release drug formulation for oral administration to said subject,” includes a core comprising a drug for release in the colon, an isolation layer coating said core, and an outer coating for providing intestinal release of said drug, said outer coating comprising an outer layer and an inner layer ([0024] through [0027])(instant claims 5, 10 & 11 - solid oral formulation). VARUM teaches that: “In preferred embodiments, the isolation layer comprises a film-forming non-ionic polymer, such as HPMC or PVA […].” ([0030]). And that: “However, in other preferred embodiments, the outer layer has a mixture of a digestible (or "first") polymeric material susceptible to attack by colonic bacteria, e.g. a polysaccharide, and the pH dependently soluble (or "second") polymeric material.” ([0031]). VARUM teaches that: “It is preferred that the digestible (or first) polymeric material comprises at least one polysaccharide selected from the group consisting of starch; amylase; amylopectin; chitosan; chondroitin sulphate; cyclodextrin; dextran; pullulan; carrageenan; scleroglucan; chitin; curdulan and levan.” ([0036] & [0056]-[0065])(instant claims 7-8). VARUM teaches that: “In preferred embodiments, the pH dependently soluble (or second) polymeric material is an anionic polymeric material, and more preferably an anionic copolymer of a (meth)acrylic acid and a (meth)acrylic acid alkyl ester.” ([0037]).
VARUM teaches that: “The second polymeric material has a pH threshold of pH 5 or above, e.g. about pH 5.5 or above, preferably about pH 6 or above and more preferably about pH 6.5 or above. The second polymeric material typically has a pH threshold of no more than about pH 8, e.g. no more than about pH 7.5 and preferably no more than about pH 7.2. Preferably, the second polymeric material has a pH threshold within the range of pH found in intestinal fluid. The pH of intestinal fluid may vary from one person to the next, but in healthy humans is generally from about pH 5 to 6 in the duodenum, from 6 to 8 in the jejunum, from about 7 to 8 in the ileum, and from about 6 to 8 in the colon.” ([0070])(instant claims 6-8). VARUM teaches the inclusion of a buffer agent(s) is usually present in the inner layer in an amount from about 0.1 wt% to about 50 wt%. ([0119]).
VARUM teaches that: “The second polymeric material is typically a film forming polymeric material such as a polymethacrylate polymer, a cellulose polymer or a polyvinyl-based polymer. Examples of suitable cellulose polymers include cellulose acetate phthalate (CAP); cellulose acetate trimellitate (CAT); Hydroxypropylmethylcellulose phthalate (HPMCP) and hydroxypropylmethylcellulose acetate succinate (HPMCAS). Examples of suitable polyvinyl-based polymers include polyvinyl acetate phthalate (PVAP).” ([0073])(instant claim 23).
VARUM teaches that: “Formulations according to embodiments of the present invention have superior colonic-release properties over comparative coatings designed for site-specific release in the colon. In this connection, drug release from formulations according to embodiments of the present invention appears to be accelerated in the colon when compared to comparative colonic release formulations. The Inventors are confident that other formulations within the scope of the invention should also have superior release properties over comparative coatings designed for site-specific release in the small intestine, and proximal small intestine in particular. Broadly speaking, the region of the intestine in which initial release occurs can be controlled by the choice of pH dependently soluble polymeric material.” ([0033]). And that: “Without wishing to be bound by any particular theory, the Inventors believe that, once intestinal fluid or gastrointestinal fluid penetrates the outer layer, the inner layer begins to dissolve before the outer layer to form a fluid region between the core and the outer layer. The fluid region not only
facilitates dissolution and/or disintegration of the outer layer from the inside, but also softens and begins to break up the core so that, when the outer layer degrades, the drug is released from the core more quickly.” ([0034])(instant claim 22).
VARUM teaches that: “The identity of the drug(s) in the formulation obviously depends on the condition to be treated. In this connection, the formulation has particular application in the treatment of IBD (including Crohn's disease and ulcerative colitis); IBS; constipation; diarrhea; infection; and carcinoma, particularly colon or colorectal cancer.” ([0164]). And that: “For the treatment or prevention of IBD, the formulation may comprise at least one drug selected from the group consisting of anti-inflammatory agents […] and biological agents including peptides, proteins and antibody fragments. Suitable examples of biological agents include alkaline phosphatase and anti-TNF antibodies such as infliximab, adalimumab, certulizumab pegol, golimumab and ustekinumab.” ([0165])(instant claims 1, 4, “the protein is an antibody or fragment thereof”).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of VARUM is that VARUM does not expressly teach the peptide the dipeptide species carnosine (instant claims 1-2, 10-11), the inclusion of the enzyme inhibitor aprotinin (instant claims 1 & 3, 10-11); or the addition of diglycine.
MOLLER teaches combination therapy with IL-21 analogous (title, abstract, see whole document), and including antibodies ([0080], [0229]). MOLLER teaches the pharmaceutical formulations for oral administration such as tablets, and including enteric coatings ([0323]). MOLLER teaches inclusion of a buffering agent such as glycylglycine (syn. diglycine1). Therefore, it would have been prima facie obvious to include diglycine as a buffering agent (so-called Good’s Buffer), as a suitable species of buffer agent per the teachings of VARUM.
MADSEN teaches novel acetylated insulin analogues (title, abstract, see whole document), and particularly teaches that: “The term "stabilizer" as used herein refers to chemicals added to peptide containing pharmaceutical compositions in order to stabilize the peptide, i.e., to increase the shelf life and/or in-use time of such compositions. Examples of stabilizers used in pharmaceutical formulations are L-glycine, L-histidine, arginine, glycylglycine, ethylenediamine, citrate, EDTA, zinc, sodium chloride, polyethylene glycol, carboxymethylcellulose, and surfactants and antioxidants like alfa-tocopherol and I-ascorbic acid.” [emphasis added]([0288], [0304]). Therefore, it would have been prima facie obvious to include glycylglycine (syn. diglycine) as a stabilizer in a peptide (e.g. antibody) pharmaceutical formulation, as suggested by, MADSEN.
Guiotto et al. teaches that: “Despite all these recognised or just postulated activities, however, carnosine is probably best known as a non-enzymatic free-radical scavenger and a natural antioxidant. Erin and colleagues [30] demonstrated that carnosine directly interacts with molecular products of lipid peroxidation, as well as superoxide anion radicals and hydroxyl radicals. Studies showed that carnosine can: scavenge aldehydes (from glucose to the highly toxic malondialdehyde) [4, 31, 32] and aldehyde-induced toxicity in cultured cells [32, 33] and in vivo [34]; inhibit aldehyde-induced protein-protein and DNA-protein cross-linking, and the formation of protein carbonyl groups [32, 35]; protect proteins against glycation [31, 32, 35-37]; and react with protein carbonyl groups forming “carnosinylated” proteins (Fig. 2).” (p. 2294, col. 1, last paragraph).
PRAVADA teaches that: “The subject invention pertains to materials and methods for the prevention and treatment of disease conditions associated with oxidative stress or a compromised reducing environment, including inflammatory bowel diseases such as Crohn's disease and ulcerative colitis.” (abstract). PRAVADA teaches solid formulations for oral administration ([0068] & [0090]) the inclusion of “compounds that help protect the proteins from oxidation and degradation (e.g., L-carnosine)” ([0085]). Therefore, it would have been prima facie obvious to include L-carnosine in as a stabilizer in a peptide (e.g. antibody) pharmaceutical formulation, as suggested by, Guiotto et al. and PRAVDA.
HESLET teaches “compositions comprising granulocyte-macrophage colony-stimulating factor and fosfomycin for the treatment, prevention or alleviation of an inflammatory bowel disease such as Crohn's disease, ulcerative colitis or necrotizing enterocolitis of newborn and premature infants by administration of the compositions into the intestinal lumen.” (abstract, see whole document). HESLET teaches that: “The present invention provides compositions comprising granulocyte-macrophage colony-stimulating factor (GM-CSF) for prophylaxis, pre-emptive therapy and/or treatment of inflammatory bowel disease (IBD). The term IBD includes Crohn's disease (CD) and ulcerative colitis (UC) as well as necrotizing enterocolitis (NEC), which especially affects premature neonates. Other aspects of the invention are methods of treatment or prevention of relapse using the compositions described herein.” (p. 1, lines 5-11).
HESLET teaches that: “If proteolytic breakdown of GM-CSF proves to be an obstacle to achieving effective intraluminal administration of GM-CSF, administration of the active substance can be combined with the admixture of protease inhibitors such as soybean trypsin inhibitor and/or aprotinin.” [emphasis added](p. 6, lines 12-15). HESLET teaches that: “Protease inhibitors such as aprotinin and/or soybean trypsin inhibitor that are compatible with in-vivo use in the intestinal lumen may be added to the compositions and formulations of the present invention to limit the breakdown of GM-CSF or functional variants or homologues thereof, so that effective concentrations are obtained in the intestinal lumen and mucosa.” (p. 26, lines 13-17).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce a delayed release solid oral formulation for delivery to the lower gastrointestinal tract including an antibody, e.g., an anti-TNF antibodies such as infliximab, as suggested by VARUM, and further to include carnosine “to inhibit aldehyde-induced protein-protein and DNA-protein cross-linking, and the formation of protein carbonyl groups [32, 35]; protect proteins against glycation” as suggested by Guiotto et al. and/or to “protect the proteins from oxidation and degradation (e.g., L-carnosine)” as suggested by PRAVADA, and further to include aprotinin “to limit the breakdown of GM-CSF or functional variants or homologues thereof”, as suggested by HESLET, and to include glycylglycine (i.e. diglycine) as a pH buffering agent and/or as a peptide stabilizer as suggested by MOLLER and MADSEN, respectively.
From the 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 because it would have required no more than an ordinary level of skill in the art to include carnosine, and aprotinin in the formulation of VARUM. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
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(a).
Response to Arguments:
Applicant's arguments filed 09/09/2025 have been fully considered but they are not persuasive.
Applicant argues that: “a POSA would not combine Varum, Moller, and Madsen to reach the use of diglycine for stabilizing an antibody or antibody fragment in the lower gastrointestinal tract of a subject as required by the claims. The buffer referred to in Moller relates to aqueous solutions, and the buffer/stabilizer referred to in Madsen relates to the preparation of powered formulations. It is not clear how the teachings of either reference fit in with the specific requirements of the coating of Varum. Most critically, both Moller and Madsen are silent about the need to stabilize an antibody or antibody fragment in the lower gastrointestinal tract of a subject. Because of this, Applicant respectfully asserts that there is no teaching or guidance from Varum, Moller, and Madson that would allow a POSA to specific select diglycine (a.k.a. glycylglycine) from the numerous other possibilities, let alone with a reasonable expectation that such an addition would be successful in achieving the claimed purpose of stabilizing an antibody or antibody fragment in the lower gastrointestinal tract of a subject.” (p. 9, 2nd paragraph).
In response the examiner argues that MPEP §2145(II) makes clear that “Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention.” The instantly rejected claims include any amount of “an active ingredient comprising an antibody or fragment thereof” and any amount of “carnosine” (D-carnosine or L-carnosine) and any amount of “diglycine”. The stability of a pharmaceutical composition is a property of the pharmaceutical composition, and in the instant case the instant Specification discloses that: “The one or more di-peptides and optionally the enzyme inhibitor cause at least 5% of the protein present to remain intact after 4 hours in the gastrointestinal fluid. Preferably at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90% 95% or more of the protein remains intact.” (p. 7, lines 8-11). The instant Specification does not define the claim term “stabilize” and is properly interpreted as any measurable improvement in stability of the “antibody or fragment thereof”. MPEP §2112.01(II) makes clear that: “A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.” In the instant case any amount of “an antibody or fragment thereof” in combination with any amount of “carnosine” (D-carnosine or L-carnosine) and any amount of “diglycine” necessarily results to “stabilize the active ingredient (i.e. [an antibody or fragment thereof]) in the lower gastrointestinal tract of a subject.”
In response to Applicant pointing to their motivation for combining the “an antibody or fragment thereof” with “carnosine” and “diglycine”, that is, “Most critically, both Moller and Madsen are silent about the need to stabilize an antibody or antibody fragment in the lower gastrointestinal tract of a subject. […] there is no teaching or guidance from Varum, Moller, and Madson that would allow a POSA to specific select diglycine (a.k.a. glycylglycine) from the numerous other possibilities, let alone with a reasonable expectation that such an addition would be successful in achieving the claimed purpose of stabilizing an antibody or antibody fragment in the lower gastrointestinal tract of a subject.” MPEP §2144(IV) makes clear that: “The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant.” Therefore, arguments directed at the results, absent claims commensurate with a showing of unexpected results, are not considered a convincing basis for patentability of the instant claim(s).
Regarding a reasonable expectation of success, the examiner argues that the simple combination of three ingredients – “an antibody or fragment thereof” with “carnosine” and “diglycine” – would have required no more than an ordinary level of skill in the art pertaining to pharmaceutical formulation with a reasonable expectation of success that the combination would have been stable.
Applicant further argues that: “Additionally, should a POSA manage to select diglycine anyway - which Applicant in no way admits - di glycine alone doesn't work for this purpose. As demonstrated in the Declaration of Vipul Yadav, which is resubmitted the Office as Exhibit A, the addition of diglycine alone to the anti-TNF alpha monoclonal antibody infliximab in human fecal slurry did not improve the antibody's stability (Dr. Yadav notes that results show "that infliximab alone was degraded at 2h (20%) and 4h (50%) and addition of two di peptides alone (diglycine and L-carnosine) did not improve the human colonic stability of infliximab." (Exhibit A at para. 7.). The exact numbers can be seen in Table 1 and Table 2 of Exhibit A The recovery of IFX at 2 hours in human fecal slurry was an average of 81 %, but the addition of diglycine reduced the recovery to an average of 78%. (Id. at Table 1.) The recovery of IFX at 4 hours in human fecal slurry was an average of 52%, but the addition of diglycine reduced the recovery to an average of 50%. (Id. at Table 2.)
In response the examiner argues the prior art recognizes the species diglycine (glycylglycine) as a buffering agent suitable used in pharmaceutical compositions, and as a stabilizer of peptides. In response to Applicants allegation of unexpected results, MPEP §716.02 makes clear that: “Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected.” Carnosine is clearly taught as a natural antioxidant and diglycine is taught as a known pharmaceutical pH adjusting agent and stabilizer, therefore one of ordinary skill would have expected more than an additive effect when used together as the mechanism of action is taught as different and distinct for carnosine and diglycine. Arguendo, the results were considered unexpected, the claims are not considered commensurate with the results as none of the currently presented claims are limited to the constituent active ingredient infliximab in combination with L-carnosine and diglycine, and particularly the amounts required for the alleged unexpected result. MPEP §716.02(d).
Although the record may establish evidence of secondary considerations which are indicia of nonobviousness, the record may also establish such a strong case of obviousness that the objective evidence of nonobviousness is not sufficient to outweigh the evidence of obviousness. Newell Cos. v. Kenney Mfg. Co., 864 F.2d 757, 769, 9 USPQ2d 1417, 1427 (Fed. Cir. 1988), cert. denied, 493 U.S. 814 (1989); Richardson-Vicks, Inc., v. The Upjohn Co., 122 F.3d 1476, 1484, 44 USPQ2d 1181, 1187 (Fed. Cir. 1997). Applicant is reminded that the submission of objective evidence of patentability does not mandate a conclusion of patentability in and of itself. In re Chupp, 816 F.2d 643, 2 USPQ2d 1437 (Fed. Cir. 1987).
Applicant further argues that: “However, a POSA would recognize that Guiotto simply does not teach or suggest that carnosine can stabilize and inhibit the degradation of an antibody within the environment of the gastrointestinal tract. Further, the Office offers no explanation as to why a POSA would combine Guiotto with Varum to reach the carnosine element of the present claims.” (p. 10, last paragraph through p. 11, line 2). And that: “Carnosine is mentioned as a possible excipient in these compositions as a compound that protects the proteins from oxidation and degradation, presumably in the compromised reducing environment associated with the presence of hydrogen peroxide causing inflammatory bowel disease. However, a POSA would recognize that, like Guiotto, Pravda does not teach or suggest that carnosine can stabilize and inhibit the degradation of an antibody with the environment of the gastrointestinal tract. And, again like Guiotto, the Office offers no explanation as to why a POSA would combine Pravda with Guiotto or Varum to reach the carnosine element of the present claims.” (p. 11, 2nd paragraph). And further that: “Most critically, both Guiotto and Pravda are silent about the need to stabilize an antibody or antibody fragment in the lower gastrointestinal tract of a subject. Because of this, Applicant respectfully asserts that there is no teaching or guidance from Varum, Guitto, and Pravda that would allow a POSA to specific select carnosine for inclusion in the formulation of Varum, let alone with a reasonable expectation that such an addition would be successful in achieving the claimed purpose of stabilizing an antibody or antibody fragment in the lower gastrointestinal tract of a subject.” (paragraph bridging pp. 11-12).
In response the examiner argues that prior art does not need to recognize Applicants results to produce the claimed combination of three ingredients – “an antibody or fragment thereof” with “carnosine” and “diglycine” (MPEP §2144(IV) and §2145(II)). The examiner maintains that the prior art recognizes the species diglycine (glycylglycine) as a buffering agent suitable used in pharmaceutical compositions, and as a stabilizer of peptides. In response to Applicants allegation of unexpected results, MPEP §716.02 makes clear that: “Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected.” Carnosine is clearly taught as a natural antioxidant and diglycine is taught as a known pharmaceutical pH adjusting agent and stabilizer, therefore one of ordinary skill would have expected more than an additive effect when used together as the mechanism of action is taught as different and distinct for carnosine and diglycine.
Applicant further argues that: “As noted, none of Moller, Madson, Guiotto, and Pravda are silent about the need to stabilize an antibody or antibody fragment in the lower gastrointestinal tract of a subject using either diglycine or carnosine, respectively. Further none of the references, including Varum, teach or suggest why a POSA would not only select diglycine or carnosine individually, but the two in combination. Finally, as noted from data shown in Exhibit A, diglycine and carnosine, individually, do not work for the purpose of stabilizing an antibody or antibody fragment in the lower gastrointestinal tract of a subject - they make the antibody less stable in the test. (Exhibit A at Tables 1 and 2).” (p. 13, 3rd paragraph). And that: “ Accordingly, Applicant respectfully disagrees with the Offices general allegations of obviousness. A POSA, in light of the combination of the cited art, would not readily select diglycine or carnosine, let alone in combination, because there is not clear teaching or suggestion to select (from the many alternative possibilities) and use these proteins in the formulation of Varum. Respectfully, merely stating that these elements are generally used in pharmaceutical compositions as stabilizers or buffers, without more support from the cited art as to why they would fit with the teachings of Varum or work successfully in the lower gastrointestinal tract, does not cure the requirement to explain why a POSA would be able to select these molecules without an undo amount of experimentation. Instead, this appears to be a selection guided by hindsight, where choosing diglycine and carnosine in combination appears obvious only because of the present application and claims. While the Courts have recognized that a certain about of hindsight is inherent in any obviousness rejection, using the specification and claims as a guide to reach the claimed invention is not permitted.” (paragraph bridging pp. 13-14).
The examiner maintains that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce a delayed release solid oral formulation for delivery to the lower gastrointestinal tract including an antibody, e.g., an anti-TNF antibodies such as infliximab, as suggested by VARUM, and further to include carnosine “to inhibit aldehyde-induced protein-protein and DNA-protein cross-linking, and the formation of protein carbonyl groups [32, 35]; protect proteins against glycation” as suggested by Guiotto et al. and/or to “protect the proteins from oxidation and degradation (e.g., L-carnosine)” as suggested by PRAVADA, and further to include aprotinin “to limit the breakdown of GM-CSF or functional variants or homologues thereof”, as suggested by HESLET, and to include glycylglycine (i.e. diglycine) as a pH buffering agent and/or as a peptide stabilizer as suggested by MOLLER and MADSEN, respectively.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant further argues that: “Finally, Applicant restates again the unexpected results as demonstrated in the Declaration of Vipul Yadav (Exhibit A). Briefly, Dr. Yadav explains that a human colonic model was prepared as described in the present specification (Id. at paragraph 5). The stability of anti-TNF alpha monoclonal antibody, infliximab (IFX), in human fecal slurry, with and without the di peptides diglycine and/or carnosine was investigated at both 2 hour and 4 hour time points (Id. at paragraph 6) and the data is shown at the end of the declaration.” (p. 14, last paragraph).
In response to Applicants allegation of unexpected results, MPEP §716.02 makes clear that: “Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected.” Carnosine is clearly taught as a natural antioxidant and diglycine is taught as a known pharmaceutical pH adjusting agent and stabilizer, therefore one of ordinary skill would have expected more than an additive effect when used together as the mechanism of action is taught as different and distinct for carnosine and diglycine. Arguendo, the results were considered unexpected, the claims are not considered commensurate with the results as none of the currently presented claims are limited to the constituent active ingredient infliximab in combination with L-carnosine and diglycine in any specific amount or range, and particularly the amounts required for the alleged unexpected result. MPEP §716.02(d). The examiner notes that the 6.6 mg/mL for diglycine and the 11.25 mg/mL of L-Carnosine are both about 50 mM.
Although the record may establish evidence of secondary considerations which are indicia of nonobviousness, the record may also establish such a strong case of obviousness that the objective evidence of nonobviousness is not sufficient to outweigh the evidence of obviousness. Newell Cos. v. Kenney Mfg. Co., 864 F.2d 757, 769, 9 USPQ2d 1417, 1427 (Fed. Cir. 1988), cert. denied, 493 U.S. 814 (1989); Richardson-Vicks, Inc., v. The Upjohn Co., 122 F.3d 1476, 1484, 44 USPQ2d 1181, 1187 (Fed. Cir. 1997). Applicant is reminded that the submission of objective evidence of patentability does not mandate a conclusion of patentability in and of itself. In re Chupp, 816 F.2d 643, 2 USPQ2d 1437 (Fed. Cir. 1987).
Conclusion
Claims 1-3, 5-11 and 22-28 are pending and have been examined on the merits. Claims 1-3, 5-11 and 22-28 are rejected under 35 U.S.C. 103. No claims allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IVAN A GREENE whose telephone number is (571)270-5868. The examiner can normally be reached M-F, 8-5 PM PST.
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/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619
1 PubChem entry for Glycylglycine (CDI-11163), §Depositor Supplied Synonyms, retrieved on 10/15/2025, pp. 1-4, see entry Nos. 1 & 3.