DETAILED ACTION
Status of the Claims
Claims 1-3, 6-16, 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 Claims 12-16, 18, 20 and 21 have been withdrawn based upon Restriction/Election as discussed below.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, 6-11 and 22-28 are being examined on the merits in the instant application.
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All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.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 05/15/2020, the filing date of the PCT/EP2020/063728, the examiner finds no support in GB1906917.8 for the amount of carnosine (50-5000mg), the amount of diglycine (50-5000mg) as recited in instant claims 1, 10 & 11).
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 24-28 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Instant claim 24 depends from claim 3 which in depends from claim 2 which depends from claim 1, and claim 1 requires specific amounts of carnosine and diglycine, and claim 3 requires a specific amount of aprotinin, claim 1 further requires that “an active ingredient comprising an IgG monoclonal antibody or fragment thereof” which is narrower in scope than “an antibody or fragment thereof”. Claim 24 therefore does not further limit the subject matter of the parent claim(s).
Instant claim 25 recites “comprising an antibody or fragment thereof, carnosine, diglycine, and an enzyme inhibitor.” Claim 25, depends from claim 10 reciting specific amounts of carnosine and diglycine, and “an active ingredient comprising an IgG monoclonal antibody or fragment thereof”. Therefore, claim 25 only further limits the subject matter “and an enzyme inhibitor” and is broader in scope with respect to the “an antibody or fragment thereof”, and does not further limit the scope of carnosine and diglycine, which are both required by the parent claim.
Claim 26 depends from claim 25 and recites “an antibody fragment thereof, carnosine, diglycine, and 50-5000 mg aprotinin.” Regarding the recited “an antibody fragment thereof, carnosine, diglycine,” the limitations do not further limit the parent claim(s), as discussed above.
Claim 27 recites “comprising an antibody or fragment thereof, carnosine, diglycine, and an enzyme inhibitor.” Claim 27, depends from claim 11 reciting specific amounts of carnosine and diglycine, and “an active ingredient comprising an IgG monoclonal antibody or fragment thereof”. Therefore, claim 27 only further limits the subject matter “and an enzyme inhibitor” and is broader in scope with respect to the “an antibody or fragment thereof”, and does not further limit the scope of carnosine and diglycine, which are both required by the parent claim.
Claim 28 depends from claim 27 and recites “an antibody fragment thereof, carnosine, diglycine, and 50-5000 mg aprotinin.” Regarding the recited “an antibody fragment thereof, carnosine, diglycine,” the limitations do not further limit the parent claim(s), as discussed above.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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, 6-11 and 22-28 are 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 in a liquid, solid or semi-solid form suitable for oral or rectal administration comprising an active ingredient comprising an IgG monoclonal antibody or fragment thereof, 50-5000 mg carnosine, and 50-5000 mg diglycine; wherein the carnosine and diglycine cause at least 40% of the antibody or fragment thereof to remain intact after 4 hours in the gastrointestinal fluid of a subject (instant claim 1). Applicant further claims the solid dosage form 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 IgG monoclonal antibody or fragment thereof, 50-5000 mg carnosine, and 50-5000 mg diglycine, wherein the carnosine and diglycine cause at least 40% of the antibody or fragment thereof to remain intact after 4 hours in the gastointestinal fluid of a subject (instant claim 10).
Applicant claims a solid dosage form for oral administration comprising: a core comprising: an active ingredient comprising an IgG monoclonal 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, “an active ingredient comprising an IgG monoclonal 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.
Regarding the amount of diglycine (glycylglycine), VARUM teaches inclusion of a buffer agent, “The buffer agent(s) is usually present in the inner layer in an amount from about 0.1 wt% to about 50 wt%.” ([0116]-[0119]). And teaches Tablet Cores of 400 mg, 800 mg and 1200 mg, which encompasses the claimed amount of diglycine (e.g. 20% of 400 mg is 80 mg, and 5% of 1200 mg is 60 mg) (MPEP §2145.05(I)). Additionally, given that MADSEN teaches diglycine as a peptide stabilizer and VARUM teaches peptides including antibodies such as infliximab and adalimumab ([0165]), it would have been prima facie obvious to optimize the amount of diglycine for stability of the peptide/protein drug of VARUM (MPEP §2145.05(II)).
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) […] 1,000 mg L-carnosine, […]” ([0085]) (MPEP §2145.05(I)). 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). given that HESLET teaches aprotinin as a protease inhibitor for in-vivo use in the intestinal lumen, and VARUM teaches oral delivery of antibodies such as infliximab and adalimumab ([0165]), it would have been prima facie obvious to optimize the amount of aprotinin for stability of the antibody drug of VARUM (MPEP §2145.05(II))(instant claims 3, 26 & 28).
Regarding the limitation: “wherein the carnosine and diglycine cause at least 40% of the antibody or fragment thereof to remain intact after 4 hours in the gastointestinal fluid of a subject” (instant claims 1, 10 & 11), the prior art suggests the combination of L-carnosine, diglycine in an oral delivery of antibodies such as infliximab and adalimumab. And therefore suggest the same combination of constituent ingredients, and the result of “at least 40% of the antibody or fragment thereof to remain intact after 4 hours in the gastointestinal fluid of a subject” would have been satisfied by the same (MPEP §2112.01(II) - Products of identical chemical composition can not have mutually exclusive properties).
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 06/22/2026 have been fully considered but they are not persuasive.
Applicant argues that (i) a POSA would not modify Varum with diglycine with any expectation of success (p. 7, item i), and particularly that: “Read properly, a POSA would easily recognize that Moller is listing buffers for aqueous solutions of IL-21 or any other compound as mentioned above, and not buffers for the inner layer of an outer coating of an oral formation as taught by Varum. A POSA would also recognize that (1) an antibody isn't even a required element of the teaching of Moller (only IL-21 is) and (2) Moller is silent about the need to stabilize an antibody or antibody fragment in the lower gastrointestinal tract of a subject.” (p. 8, 4th paragraph). And further that: “A POSA would recognize that Madsen is not teaching buffers and stabilizers for the inner layer of an outer coating of an oral formation as taught by Varum. A POSA would also recognize that (1) these buffers and stabilizers are not a required element, as the insulin analogues exhibit their resistance towards proteases due to amino acid modifications from normal insulin protein, (2) Madsen is about insulin analogs, not antibodies, and (3) Madsen is silent about the need to stabilize an antibody or antibody fragment in the lower gastrointestinal tract of a subject.” (p. 9, 1st paragraph).
In response the examiner argues that VARUM clearly teaches the inclusion of a buffering agent of which diglycine was a known species in the art to which the invention pertains. And furthermore the inclusion of a buffering agent as a solid in a solid formulation is clearly obvious to achieve a pH buffer effect upon administration and release in the aqueous environment of the patient. The examiner notes that diglycine is a solid at room temperature/pressure. Additionally, VARUM clearly teaches including an IgG monoclonal antibody such as infliximab, adalimumab, certulizumab pegol, golimumab and ustekinumab. ([0165]). A person having an ordinary level of skill in the art to which the invention pertains would have know how to combine a buffer agent/stabilizer such as diglycine with a monoclonal antibody such as infliximab in the dosage form of VARUM with a reasonable expectation of success. The examiner argues that while insulin is not an IgG monoclonal antibody, both insulin and IgG monoclonal antibodies such as infliximab are proteins. The other common factor is that MADSEN and VARUM is the oral administration of protein drugs, MADSEN teaching that: “The oral route is by far the most widely used route for drug administration and is in general very well accepted by patients, especially for chronic therapies. Administration of therapeutic peptides or proteins is however often limited to parenteral routes rather than the preferred oral administration due to several barriers such as enzymatic degradation in the gastrointestinal (GI) tract and intestinal mucosa, drug efflux pumps, insufficient and variable absorption from the intestinal mucosa, as well as first pass metabolism in the liver.” ([0003]). Thus, it would have been prima facie obvious to utilize a stabilizer for an oral protein drug formulation, as suggested by MADSEN in order to improve the stability of the oral protein drug formulation.
Applicant further 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, let alone in an amount that results in the concentration of at least 50mM of diglycine in the lower gastrointestinal tract of a subject. The buffer referred to in Moller relates to aqueous solutions, and the buffer/stabilizer referred to in Madsen relates to the preparation of powdered 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, let alone an amount that results in the concentration of at least 50mM. 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 §2144(IV) - 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. In the instant case the claims are directed to compositions of matter and the delivery to the lower gastrointestinal tract is an intended use. Regarding the selection of diglycine (a.k.a. glycylglycine), the VARUM clearly teaches inclusion of a buffer and diglycine (a.k.a. glycylglycine) was a known species of the same usable with oral protein delivery per MADSEN and MOLLER (MPEP §2144.07).
Applicant further argues that “should a POSA manage to select diglycine anyway- which Applicant in no way admits - diglycine alone doesn't work for this purpose. As demonstrated in the Declaration of Vipul Yadav, which is resubmitted to 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 dipeptides 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.)” (paragraph bridging pp. 9-10).
In response the examiner again argues that the that MPEP §2144(IV) - 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. In the instant case the claims are directed to compositions of matter and the delivery to the lower gastrointestinal tract is an intended use. Regarding the selection of diglycine (a.k.a. glycylglycine), the VARUM clearly teaches inclusion of a buffer and diglycine (a.k.a. glycylglycine) was a known species of the same usable with oral protein delivery per MADSEN and MOLLER (MPEP §2144.07). The prior art clearly does not have to suggest Applicants disclosed results to properly support a prima facie case of obviousness. The prior art teaches the diglycine as a buffer/stabilizer but clearly does not teach Applicants actual results. This does not suggest patentability of the compositions of matter in the instant case, as the combination of prior art suggests the claimed invention.
Applicant argues that (ii) a POSA would not modify Varum with carnosine with any expectation of success (p. 10, item ii), and particularly 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, let alone in an amount that results in the concentration of at least 50mM in the lower gastrointestinal tract as claimed. 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. 11, 1st paragraph). And that: “Pravda teaches one embodiment in which an oral composition of the invention comprises alpha-lipoic acid, and/or N-acetyl-L-cysteine (N-A-C), and/or L-glutamine (Id. at paragraph [0085]). 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 within 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: “Applicant respectfully asserts that a POSA would not combine Varum, Guiotto, and Pravda to reach the use of carnosine for stabilizing an antibody or antibody fragment in the lower gastrointestinal tract of a subject as required by the claims.” (p. 11, last paragraph).
In response the examiner argues that VARUM clearly suggest including an IgG monoclonal antibody such as infliximab, adalimumab, certulizumab pegol, golimumab and ustekinumab ([0165]) in the oral formulations for treatment of IBD (including Chron’s Disease) ([0164]-[0165]). A person having ordinary skill in the art would have recognized these as protein drugs which are suggested to be stabilized by Guiotto et al. teaching 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). And PRAVDA clearly teaches including: “compounds that help protect the proteins from oxidation and degradation (e.g., L-carnosine),” ([0085]). Therefore, one of ordinary skill in the art would have recognized the ability of L-carnosine to stabilize protein formulations and included L-carnosine in the compositions of VARUM for the same reason. MPEP §2144-II - The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination. Applicant again argues that the carnosine alone does not work for the purpose of stabilizing the antibody in the lower gastrointestinal tract (p. 12, paragraphs 1-2).
In response to Applicants arguments that “carnosine can stabilize and inhibit the degradation of an antibody within the environment of the gastrointestinal tract”, the examiner again argues that the that MPEP §2144(IV) - 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. The prior art teaches the L-carnosine as a stabilizer of proteins but clearly does not teach Applicants actual results. This does not suggest patentability of the compositions of matter in the instant case, as the combination of prior art suggests the claimed invention.
Applicant further argues that (iii) a POSA would not reach the claimed combination of diglycine and carnosine with any reasonable expectation of success (p. 13, item iii), and particularly that “To reach the claims, a POSA would need to select for both diglycine and carnosine, each presented in an amount resulting in a concentration of at least 50mM in the lower gastrointestinal tract of a subject, with a reasonable expectation of success of achieving at least 40% of the antibody or fragment thereof to remain intact after 4 hours in the gastrointestinal fluid of said subject.” (p. 13, 1st paragraph). And 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).” (paragraph bridging pp. 13-14).
In response the examiner argues that the claimed combination of carnosine and diglycine with an IgG monoclonal antibody or fragment thereof would have been prima facie obvious and the result would have been at least 40% of the antibody or fragment thereof to remain intact after 4 hours in the gastrointestinal fluid of said subject. Particularly, the prior art suggests the combination of L-carnosine, diglycine in an oral delivery of antibodies such as infliximab and adalimumab. And therefore suggest the same combination of constituent ingredients, and the result of “at least 40% of the antibody or fragment thereof to remain intact after 4 hours in the gastointestinal fluid of a subject” would have been satisfied by the same (MPEP §2112.01(II) - Products of identical chemical composition can not have mutually exclusive properties).
Applicant further agues that (iv) Applicant has shown unexpected results with the combination of diglycine and carnosine (p. 15, item iv), and particularly “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 dipeptides 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. 15, 1st paragraph). And that: “Dr. Yadav notes that results show "that infliximab alone was degraded at 2h (20%) and 4h (50%) and addition of two dipeptides alone (diglycine and L-carnosine) did not improve the human colonic stability of infliximab. In fact, the addition of L-carnosine alone is markedly worse that infliximab alone." (Id. at paragraph 7). However, Dr. Yadav states that "the addition of diglycine and L-carnosine together showed a surprising improvement in stability at both 2h and 4h timepoints by 13% and 12% respectively, clearly showing a synergistic effect of the two dipeptides in preventing proteolytic degradation of infliximab in human colonic environment." (Id.) Dr. Yadav concludes that the "experiment demonstrates the need for the use of diglycine and L-carnosine together in an oral formulation to allow sufficient stabilization of infliximab, leading to potential uptake both into the colonic tissue and/or systemic circulation in order to treat various chronic inflammatory diseases such as inflammatory bowel disease, psoriasis and arthritis." (Id.)”
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). The examiner further notes that the MPEP requires any unexpected results to be commensurate with the results shown: "Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range." (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).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning (p. 17, v. Conclusion), 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).
Citation of Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Muhammed (“The Best IgG Subclass for the Development of Therapeutic Monoclonal Antibody Drugs and their Commercial Production: A Review,” Immunome Research, Vol. 16, Issue. 1, No. 173, pp. 1-12) is cited as teaching that “Most of the clinically available monoclonal antibody (mAbs) drugs are Immunoglobulin G's (IgG's). The variability of the IgG subclasses is in the amino acid content of the hinge region which forms the basis of their stability and suitability for therapeutics development.” (abstract, see whole document).
Conclusion
Claims 1-3, 6-11 and 22-28 are pending and have been examined on the merits. Claims 24-28 are rejected under 35 U.S.C. 112(d) and claims 1-3, 6-11 and 22-28 are rejected under 35 U.S.C. 103. No claims allowed at this time.
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 IVAN A GREENE whose telephone number is (571)270-5868. The examiner can normally be reached M-F, 8-5 PM PST.
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, David Blanchard can be reached on (571) 272-0827. 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.
/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.
Prosecution Insights