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 .
2. Applicant’s response filed on 08/27/2025 is acknowledged. The font that Applicant uses for the claim amendments cannot be recognized by the USPTO’s text recognition system. Please only use a font with solid lines.
3. Claims 1-5 and 7-16 are pending and under consideration.
4. The following rejections are necessitated by the amendment filed on 08/27/2025.
5. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
6. Claims 1-5 and 7-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicant is in possession of: a composition comprising antibodies to tumor necrosis factor alpha and functional fragments thereof, one or more pH modifiers and one or more buffer agents wherein the composition is in the form of an enema, gel, suppository or foam and wherein the composition decreases the pH in the large intestinal lumen to less than 6.5 upon rectal administration. Applicant is in possession of the particular enemas and gel described in Table 1 and Examples 12-13.
Applicant is not in possession of: a composition comprising antibodies to tumor necrosis factor alpha and functional fragments thereof and buffer agents which results in a decrease of pH in the large intestinal lumen; an oral composition for use in the topical treatment of an inflammatory bowel disease in a human patient wherein said composition comprises (a) an active agent selected from the group consisting of antibodies specific to tumor necrosis factor alpha and functional fragments thereof, in combination with (b) an amount of at least one additive selected from the group consisting of buffer agents, acidifiers and combinations thereof sufficient to decrease the pH in the large intestinal lumen of said patient wherein said composition is in the form of a solid dosage form formulated for oral administration that is coated with a coating material that prevents release of the active agent and at least one additive before entry into the ileocolonic region of the patient’s intestine; a composition comprising antibodies to tumor necrosis factor alpha and functional fragments thereof; a pH modifier and buffer agents wherein the composition is in any form other than for rectal administration as an enema, gel, suppository or foam. Applicant is not in possession of a composition for oral administration with the recited functions or for any other administration than rectal administration.
Applicant has described only a composition comprising antibodies to tumor necrosis factor alpha and functional fragments thereof, one or more pH modifiers and one or more buffer agents wherein the composition is in the form of an enema, gel, suppository or foam and wherein the composition decreases the pH in the large intestinal lumen to less than 6.5 upon rectal administration, including the particular enemas and gel described in Table 1 and Examples 12-13.
The specification describes that the provision of a TNFα antibody or a functional fragment thereof to the luminal side of the large intestinal wall at a lower than normal pH results in its effective permeation across the large intestinal wall. It has been found that a lower pH of about 6 results in an increased uptake of TNFα antibodies or functional fragments thereof across the epithelial and into the mucosal layer of the large intestinal wall, as well a deeper penetration into submucosal layer of the large intestinal wall, than a higher pH of about 7.4. Where the protective mucus layer of the gastrointestinal wall is impaired, the TNFα antibody or functional fragment thereof is taken up faster and penetrates deeper into the gastrointestinal wall, resulting in higher levels of the TNFα antibody or functional fragment thereof and effective retention.
The specification has not described any composition which can be administered in any way other than rectally for the desired effect. The specification does not describe any way that the composition can be administered orally and have the recited effect. The art of Tashima et al. (IDS filed on 06/12/2023) teaches the state of the art in oral administration of antibody formulations as of 2021. The reference teaches “Oral administration is an ideal route for mAbs. Nonetheless, proteolysis and denaturation, in addition to membrane impermeability, pose serious challenges in delivering peroral mAbs to the systemic circulation, biologically, through enzymatic and acidic blocks and, physically, through the small intestinal epithelium barrier. A number of clinical trials have been performed using oral mAbs for the local treatment of gastrointestinal diseases, some of which have adopted capsules or tablets as formulations. Surprisingly, no oral mAbs have been approved clinically.” Furthermore, no oral antibody treatments taught in the reference are directed to targeting the large intestine specifically. In addition, there are no treatments taught to change the pH at the intended site of action as well as delivery of an antibody to the tissue. As such, oral administration by way of a tablet or capsule with coatings as claimed in claims 11-12 and as described in the specification would not result in the recited function of decreasing the pH in the large intestine much less supplying the antibody to the large intestine.
This definition in the specification does not provide adequate written description for a composition that results in the decrease of a pH in the large intestinal lumen of said patient to between 5.5 and 6.5, a pH in the large intestinal lumen reading that is 6.5, that ranges from 5.7 to 6.3, or that ranges from 5.9 to 6.1 other than a composition that is directly applied to the large intestine in the form of an enema, suppository or rectal foam. The description in the specification does not provide support for any composition which can be administered to the patient in a way other than directly to the large intestine. Oral compositions which result in a pH change in the large intestine are not adequately described. Further, the specification has not adequately described a composition with a structure which will result in both a pH change and release of antibodies to the large intestine. The specification has described no such composition or formulation which will result in said effect. There is no correlation between the structure of the composition and the function of changing the pH in the large intestine, particularly to a pH of 5.5 to 6.5, and releasing antibodies to the large intestine such that the composition results in the treatment of the large intestine of an inflammatory bowel disease patient.
Applicant’s attention is drawn to the art of Nugent et al. (IDS filed on 06/12/2023) which teaches that “Gastrointestinal luminal pH data recorded by RTC in normal volunteers are shown in table 1. Luminal pH in the proximal small bowel ranges from 5.5 to 7.0 and gradually rises to 6.5–7.5 in the distal ileum. In almost every recording published there has been a fall in luminal pH from the terminal ileum to the caecum (range 5.5–7.5); pH then rises in the left colon and rectum to 6.1–7.5.” the pH of the caecum/right colon is 5.5-7.5 and the pH of the left colon/rectum is 6.5-7.5. (See Table 1, page 572, whole document). The reference teaches in
“Reduced mucosal bicarbonate secretion, increased mucosal and bacterial lactate production, and impaired SCFA absorption and metabolism may each contribute to a reduction in colonic luminal pH in patients with inflamed colonic mucosa.” (In particular, page 573). “Therapeutic implications of low colonic luminal pH in IBD Several drugs used for the treatment of ileal and colonic IBD have been formulated so as to deliver the active agent directly to the site of inflammation, thereby reducing their absorption in the proximal gastrointestinal tract and reducing systemic side effects. Some of these agents utilise pH dependent release systems (for example, Asacol, Salofalk, and budesonide) while others depend on bacterial enzymatic metabolism (sulphasalazine, olsalazine, balsalazide) which may also be affected by changes in colonic luminal pH.” (In particular, page 574). As such, the reference teaches that IBD patients actually have a lower luminal pH than normal patients. Irrespective of the pH of IBD patients specifically, the reference teaches that there is a broad range of pH in the lumen of the large intestine, both between the right and left colon generally and within each of those areas.
Using an enema would target the left colon and rectum which have a pH of 6.5-7.5 according to the information in Table 1 of Nugent, resulting in a predictable site of pH change which is distinguished from that of the proximal and distal parts of the small bowel and the caecum/right colon. This information provides further evidence that the specification has not described a composition which has been orally administered which will go through the small bowel which ranges in pH of 5.5-7.5 before reaching the caecum/right colon which has a pH that completely overlaps. The reference also teaches that the transit time is unpredictable in patients with inflammation. (In particular, page 574). The specification has not described a composition which changes the pH of the large intestine and which administers anti-TNF-alpha antibodies to the site which can be administered by any way other than by enema, suppository or rectal foam.
The specification describes that the provision of a TNFα antibody or a functional fragment thereof to the luminal side of the large intestinal wall at a lower than normal pH results in its effective permeation across the large intestinal wall. It has been found that a lower pH of about 6 results in an increased uptake of TNFα antibodies or functional fragments thereof across the epithelial and into the mucosal layer of the large intestinal wall, as well a deeper penetration into submucosal layer of the large intestinal wall, than a higher pH of about 7.4. Where the protective mucus layer of the gastrointestinal wall is impaired, the TNFα antibody or functional fragment thereof is taken up faster and penetrates deeper into the gastrointestinal wall, resulting in higher levels of the TNFα antibody or functional fragment thereof and effective retention.
The ability to decrease pH in the large intestine is a requirement of the composition and the antibodies do not perform that function, so the claims must recite the component(s) of the composition that does perform that function. The claims are not adequately described for a composition that targets the large intestine for both a pH change and delivery of antibodies other than a composition which is directly applied to the area in the form of an enema, suppository or rectal foam.
The skilled artisan cannot envision all the compositions recited in the instant claims. Consequently, conception cannot be achieved until a representative description of the structural and functional properties of the claimed invention has occurred, regardless of the complexity or simplicity of the method.
Adequate written description requires more than a mere statement that it is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC1993). The Guidelines for the Examination of Patent Application Under the 35 U.S.C.112, ¶1”Written Description” Requirement make clear that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 20001, see especially page 1106 3rd column).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant’s response filed on 08/27/2025 has been fully considered, but is not found persuasive.
Applicant argues:
At the bottom of page 4, the Examiner rejects claims 1-16 under 35 U.S.C. § 112, first paragraph, for failing to comply with the written description requirement. According to the Examiner, while Applicant has demonstrated possession of a composition comprising anti-TNF antibodies, one or more pH modifiers and one or more buffers in a form suitable for rectal administration (i.e., an enema, gel, suppository or foam), Applicant has failed to demonstrate possession of a composition for oral administration in accordance with the pending claims. Applicant respectfully disagrees.
At the outset, while the Examiner has phrased the challenge as one to written description (i.e., possession of the claimed invention), it seems she is not questioning the disclosure of oral embodiments but rather the operability of such embodiments. In other words, her concerns are more properly couched under "enablement" rather than "written description". Nevertheless, in an effort to expedite prosecution, Applicant has amended the claims to require: (1) an amount of at least one additive selected from the group consisting of buffer agents, acidifiers, and combinations thereof sufficient to decrease the luminal pH of the large intestinal lumen of a patient; (2) a coating material that prevents release of the active agent and at least one additive before entry into the ileocolonic region of the patient's intestine"; and (3) the "topical" (rather than systemic) treatment of afflicted intestinal tissues.
Notably, the prior iteration of claim 1 did not recite the requisite "at least one additive". Accordingly, the Examiner held that:"The ability to decrease pH in the large intestine is a requirement of the composition and the antibodies do not perform that function, so the claims must recite the component(s) of the composition that does perform that function." Applicant respectfully submits that the express inclusion of at least one additive that does perform the noted function serves to render moot the Examiner's assessment. To the extent that concerns may linger, it may be helpful to explain that the acidifying and/or buffering additives are the local pH modifiers. To wit, the inventive composition is formulated for oral administration but acts in a topical manner, releasing the active ingredient (and at least one additive) at a target location in the colon and imparting therapeutic benefit directly on the local tissues (as opposed to via systemic uptake). In this context, the "at least one additive" (buffers, acidifiers, combinations) potentiates the efficacy of the active agent by reducing the local pH, which in turn, "facilitates the uptake and/or penetration of the active agent into the gastrointestinal wall" (see p.16, lines 13-15). This local, targeted delivery that is critical to functionality is achieved through the inclusion of a coating material that ensures pH-dependent, time-dependent, or enzymatic-dependent degradation occurs in the large intestinal environment (as required by claim 12). None of this seems particularly out of the range of the skilled artisan to envision and fabricate. In fact, the Examiner's own reference (Nugent) states that "several drugs used for the treatment of ileal and colonic IBD have been formulated so as to deliver the active agent directly to the site ofinflammation thereby reducing their absorption in the proximal gastrointestinal tract and reducing systemic effects." (see Office Action at page 8, characterizing Nugent at p. 574).
As for the Examiner's suggestions at page 7 that "oral compositions which result in a pH change in the large intestine are not adequately described" and "oral administration by way of a tablet or capsule with coatings as claimed in claims 11-12 and as described in the specification would not result in the recited function of decreasing the pH in the large intestine much less supplying the antibody to the large intestine", Applicant respectfully disagrees.
The function of the written description requirement under the second paragraph of 35 U.S.C. § 112 is to clearly convey the subject matter that an applicant has invented as of the filing date of the application relied on. In re Barker, 559 F.2d 588, 592 n.4, 194 U.S.P.Q. 470, 473 n.4 (C.C.P.A. 1977), cert. denied, 434 U.S. 1064 (1978). The applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he was in possession of the invention, i.e., whatever is now claimed. Vas-Cath Inc. v. Mahurkar, 19 U.S.P.Q.2d 1111, 1117 (Fed. Cir. 1991). Accordingly, the standard for determining compliance with the written description requirement is "does the description clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed." In re Gosteli, 872 F.2d 1008, 1012, 10 U.S.P.Q.2d 1614, 1618 (Fed. Cir. 1989).
Herein, there is ample description of oral embodiments in the originally filed specification. See, e.g., paragraph [0120] of the published application which describes methods for manufacturing solid dosage forms "in the form of pellets, granules, microparticles, nanoparticles, mini tablets, capsules, or tablets and the like", including, e.g., buffers and acidifiers, compartments and layers, matrices and subunits, films and coatings, and sequential and selective disintegration, as well known in the art. See also paragraph [0139] which describes "coating materials that disintegrate above a specific pH, coating materials that disintegrate after a specific residence time in the gastrointestinal tract and coating materials that disintegrate due enzymatic triggers specific to the microflora of the large intestine", examples of which are reviewed in "Bansal et al. (Polim. Med. 2014, 44, 2, 109-118)". Indeed, a list of preferred coating materials (such as "Eudragit L100-55, Eudragit L30D-55, Eudragit L-100, Eudragit L12.5, Eudragit S-100, Eudragit 512,5, [and] Eudragit FS30D") is provided in paragraph [0140]. Hence, the application clearly discloses how a solid dosage form, which should be suitable for oral administration but targeted intestinal delivery, can be prepared.
In addition, as the Examiner's own reference to Nugent bears out, therapeutic antibody compositions formulated for oral administration and targeted intestinal delivery are known in the art. See also paragraph [0007] of the published application, which cites to Bhol et al. (2013) Inflamm Bowel Dis. 19(11): 2273-2281, a reference that describes in detail the oral administration of anti-TNF antibodies to mice either before or after induction of colitis. Likewise, US 8,647,626 B2 discloses compositions comprising TNF-specific antibodies for oral delivery and WO 2011/047328 describes antibody therapeutics with local activity in the digestive tract." As for the Examiner's reliance on Tashimi in support of the premise that "surprisingly no oral mAbs have been approved clinically", Applicant wishes to again remind the Examiner that the standard is possession not clinical approval. The fact that no formulations were approved clinically at the time of filing does not mean that applicant was not in possession of the claimed embodiment. To that end, the pH study of Nugent merely describes pH ranges and pH values in different subject populations. It does not show that the claimed invention is inoperable. Rather, Applicant respectfully submits that one skilled in the art would readily deem the orally administrable compositions that of the pending claim to be both amply described and enabled by the instant specification.
In sum, Applicant respectfully submits that the specificity of the instant claims coupled with the guidance and working examples in the specification not only enable those skilled in the art to make and use the invention of the pending claims without undue experimentation but further establish that the instant inventors were in possession of the now-claimed invention. Accordingly, Applicant submits that the claims as presented herewith are in compliance with the dictates of 35 U.S.C. § 112, 1st paragraph, and thus respectfully petition for withdrawal of the noted rejections in view of the amendments and remarks herein.”
Applicant’s argument that they have possession of “an oral composition for use in the topical treatment of an inflammatory bowel disease in a human patient wherein said composition comprises (a) an active agent selected from the group consisting of antibodies specific to tumor necrosis factor alpha and functional fragments thereof, in combination with (b) an amount of at least one additive selected from the group consisting of buffer agents, acidifiers and combinations thereof sufficient to decrease the pH in the large intestinal lumen of said patient wherein said composition is in the form of a solid dosage form formulated for oral administration that is coated with a coating material that prevents release of the active agent and at least one additive before entry into the ileocolonic region of the patient’s intestine”
is unpersuasive. There is no example in the specification of a single oral composition in the form of a solid dosage form formulated for oral administration that is coated with a coating material with this function. Given that this function is critical for Applicant’s invention, the specification should provide an example of an oral composition with this use.
In Yadav et al. (PTO-892; Reference U) which is Applicant’s own post-dated art from 2023 which is nearly 6 years after the priority date of the instant application the reference teaches
“In the era of biologics where IBD treatment has been transformed by potent antibody-based therapeutics, a key challenge still remains, to develop orally administered antibody medicines for chronic GI inflammation. This is primarily due to the challenges in accurate oral targeted delivery of drugs to the lower GI tract and the inherent enzymatic instability of antibodies in these harsh luminal environment. As a result, all antibody therapeutics in clinical development and on the market are available only as an injection leading to undesired adverse effects due to high systemic exposure and suboptimal therapeutic response due to insufficient antibody levels at the inflamed tissue. We have developed a suite of delivery technologies that are designed to bypass the harsher stomach and small intestinal conditions of the GI tract and achieve accurate targeted release and enzymatic stabilization of the antibody therapeutics in the colon. The delivery platform comprises of a film coating which is applied on the outside of the pill. The coating is a clinically validated polymer coating comprising of a combination of pH sensitive polymer and polysaccharide that is designed to start releasing drugs only when exposed to the correct pH and/or colonic bacteria, dramatically improving on the inconsistent colonic release profiles of solely pH-based coatings. The second component is in the core of the pill, a cocktail of amino acid-based excipients that are mixed together with the antibody and protects the drug from pancreatic and bacterial origin protease enzymes, allowing high luminal antibody concentration build-up that leads to inflamed tissue/systemic uptake through a combination of active and passive diffusion. We demonstrated in an acute DSS mouse model of colitis the effective colonic delivery and stabilization of an anti-IL6 antibody leading to superior uptake into the tissue compared IP injection. The superior tissue level demonstrated higher downregulation of target IL6. We are working to leverage the delivery technology for oral delivery of a variety of anti-inflammatory and epithelial wound healing protein modalities such as monoclonal antibodies, fusion proteins, cytokines, VHHs and peptides to allow for broad therapeutic interventions in indications such as Crohn’s disease, ulcerative colitis, pouchitis and celiac disease.”
As verified by Applicant’s own reference, compositions as claimed with the claimed functions were not known in the art at the time of invention and compositions which do have some of the claimed functions are much more complex than those recited in the instant claims. There are no examples in the art of compositions which can change the pH and release antibody at the same site. The specification does not provide adequate written description of the structure of a single composition which would have the claimed functions. The specification has not adequately described the structure of a composition which would have the claimed functions.
Furthermore, as detailed previously the composition requires an acidifier. The amended claims recite “an amount of at least one additive selected from the group consisting of buffer agents, acidifiers and combinations thereof” which does not require an acidifier.
"Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features" Ex parte Kubin (83 U.S.P.Q.2d 1410 (BPAI 2007)), at page 16. In this instant case, Applicants have not provided the requisite identifying structural features of the compositions encompassed. "Without a correlation between structure and function, the claim does little more than define the claimed invention by function" supra, at page 17.
The rejection stands for reasons of record.
7. No claim is allowed.
8. 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 extension fee 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 date of this final action.
9. Any inquiry concerning this communication or earlier communications from the examiner should be directed to NORA MAUREEN ROONEY whose telephone number is (571)272-9937. The examiner can normally be reached on M-F from 8:00am to 4:30pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner' s supervisor, Misook Yu, can be reached at telephone number (571) 272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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December 13, 2025
/Nora M Rooney/
Primary Examiner, Art Unit 1641