DETAILED ACTION
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 .
Election/Restrictions
Applicant’s election of species glial agonist “J11” without traverse, in the reply filed on 10/08/2024 is acknowledged.
Please note, for clarity of the record, Applicant’s election of the species of a glial agonist "J11" as recited in claim 34, having the following structure:
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Note: The elected species, glial agonist "J11", does not read on Formula (IV),
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as presented in claims 35 and 36. As a result, claims 35 and 36 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being to a non-elected species. Additionally, claims 38-40 recite “TLR4 agonist” which do not read on the elected species. As a result, claims 38-40 have also been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being to a non-elected species.
Pending claims 28 and 41-46 have been examined on the merits.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05/04/2026 has been entered.
Withdrawn Rejection
The rejection of claims 28, 34, 41, and 47 under 35 U.S.C. 103 as being unpatentable over Wolfs et al. (WO 2017/167974) in view of Ochoa-Cortes et al. Inflamm. Bowel. Dis. 2016 Feb.; 22(2):433-49, PubChem CID 4628 (2005-03-25), Ban et al. (Ther. Hung. 1982; 30(1):35-41), and in further view of Ribner et al. (Am. J. Trop. Med. Hyg. 1978 Jul; 27(4):840-2) is withdrawn in view of the claim cancellation.
New Grounds of Rejection due to the Applicant’s Claim Amendments
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 28 is rejected under 35 U.S.C. 103 as being unpatentable over Wolfs et al. (WO 2017/167974) in view of Ochoa-Cortes et al. (Inflamm. Bowel. Dis. 2016 Feb; 22(2):433-49), PubChem CID 4628 (2005-03-25), Ban et al. (Ther. Hung. 1982; 30(1):35-41), and in further view of Ribner et al. (Am. J. Trop. Med. Hyg. 1978 Jul; 27(4):840-2), Sylvester et al., (Ped. Surg. 2012:1187–207), and Shapera et al., (Am. J. Dis. Child. 1977;131(1):34–37).
Regarding claim 28, Wolfs (abstract) teaches a method of treating, ameliorating or preventing necrotizing enterocolitis (NEC), inflammation of the gut of a
preterm baby. Wolfs (page 3, line 20-23) teaches the treatment comprising administration of probiotic bacteria.
Wolfs, however, does not teach TLR4, BDNF and enteric glial cells (ECG).
Regarding TLR4, BDNF and ECG, Ochoa-Cortes (page 433-437) teaches ECGs are central regulators of gut homeostasis and inflammatory responses through molecular signaling involving TLR4, BDNF, and interaction with bacteria, as an example. Ochoa-Cortes (page 433-437) teaches that bacterial components activate TLRs including TLR4 on ECGs, leading to inflammation. Ochoa-Cortes (page 437 and 445) also teaches reactive ECGs increases BDNF expression, which serves as a protective factor that helps reducing inflammation-driven damage by inhibiting cell apoptosis during gut inflammation. Ochoa-Cortes (page 445) teaches bacteria and bacterial infection activates ECGs, leading to inflammation and altered gut function. Given that antibiotics are agent that act against bacteria, a POSITIA would recognize that using antibiotic might reduce EGC activation and inflammatory response, leading to a reduction of TLR4 signaling.
The combined teachings of Wolfs and Ochoa-Cortes do not teach a glial agonist.
However, PubChem CID 4628 discloses that the following compound
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was part of a chemical library on or about 03-25-2005. PubChem CID 4628 identifies the compound as oxolinic acid that is similar to that of the elected species, glial agonist “J11”. PubChem CID 4628 discloses that the compound is a synthetic antibiotic belonging to the quinolone class and is used to treat bacterial infection, including urinary tract infections. PubChem CID 4628, however, does not explicitly teach oxolinic acid to treat NEC.
However, Ribner (abstract; page 840-841) teaches the use of oxolinic acid to treat gastrointestinal issues cause by bacterial infections, such as those involving Shigella flexneri, suggests potential application for other gastrointestinal conditions, including NEC. This is supported by Ochoa-Cortes (page 445) teaches Shigella flexneri can cause intestinal infection leading to a reactive glial cell phenotype, and production of protective factors such as BDNF. Furthermore, Ban study titled “Microbiological and clinical examinations supporting the effectivity of oxolinic acid (Gramurin) in the treatment of acute enterocolitis” indicates that the claimed approach has been explored in the past. While the full text of this article is not available, its title alone suggests that research on oxolinic acid for enterocolitis treatment predates current claims. Given NEC is a specific form of enterocolitis and gastrointestinal inflammatory diseases, thus, treatment known to be effective against acute enterocolitis or related gastrointestinal infection would be expected by a POSITA to be also effective in treating NEC. For this reason, it would have been obvious to a POSITA to combine the teachings of Wolfs, Ochoa-Cortes, Ribner, and PubChem CID 4628 to develop a glial agonist, oxolinic acid, to arrive at the claimed invention, because concept of using oxolinic as therapeutic approach to enterocolitis is not novel.
Furthermore, Sylvester (page 1187-1188) Necrotizing enterocolitis (NEC) is an acquired inflammatory disease that affects the gut of newborn or premature infants nearly exclusively. Sylvester (page 1197) teaches that NEC is associated with infection or colonization by Gram-negative enteric organisms, including E. coli, Klebsiella species, Proteus species, Staphylococcus species, Enterobacter species and enterococci. Sylvester (page 1196-1197 and 1201) discloses NEC management includes antibiotic therapy directed towards bacterial pathogens; therefore, a POSITA would have reasonably sought antibacterial agents effective against these microorganisms. This is supported by Shapera (page 34-36) demonstrating antibacterial activity of oxolinic acid against same Gram-negative organism as found in NEC, including E. coli, Klebsiella, Proteus, Enterobacter, and had been administered therapeutically in pediatric patients. Therefore, it would have been obvious with a reasonable expectation of success to a POSITA at the time of filing of the instant application to evaluate oxolinic acid for treatment of NEC-associated bacterial infections in newborn or premature infants.
Please note:
“Products of identical chemical composition cannot have mutually exclusive properties.” 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 re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01
Claims 41-43 are rejected under 35 U.S.C. 103 as being unpatentable over Wolfs, PubChem CID 4628, Ochoa-Cortes, Ban, Ribner, Shapera and Sylvester as applied to claim 28 above, in view of Aceti et. al. (Ital. J. Pediatr. 2015 Nov 14;41:89) and in further view of Russell et al. (US 2010/0074870).
Regarding claims 41-42, Wolfs (page 3, line 20-23) teaches the treatment regimen for gut inflammation or NEC in preterm baby, involved administration of probiotics. In addition, Ochoa-Cortes (page 445) teaches that probiotics restore EGC function and thereby reduce inflammation, specifically by decreasing the release of inflammatory cytokines from EGCs. This is supported by Aceti (abstract) teaches probiotics, including specific strains of Bifidobacterium, are used to treat or prevent NEC in preterm infants. Therefore, it would have been obvious to a POSITA to modify the teachings of Wolfs and Ban in view of Ochoa-Cortes and Aceti’s disclosure to include probiotic bacteria such as Bifidobacterium as part of treatment approach and arrive at the claimed invention, because the combined teachings of Wolfs, Ochoa-Cortes and Aceti demonstrate that probiotic bacteria, Bifidobacterium, play essential role to suppress inflammation associate with NEC.
Regarding claim 43, Wolfs does not explicitly teach probiotic bacteria in the claimed range of 1 x 104 CFU to about 1 x 106 CFU.
However, Aceti (page 4-8, Table 1) teaches the use of various dose of Bifidobacterium, including Lin, 2005 study using ≥ 106 CFU, approaches the upper limit of the claimed range. Aceti (page 6, Table 1) teaches Rougé, 2009 study using “Total dose: 1×108 CFU/day”, this indicates that patients are taking multiple dose doses throughout the day, and thus a single dose could potentially fall within the claimed range. This is supported by Russell (abstract; [00310]) teaches the use of Bifidobacterium longum in infant formulation in “the range of about lxl04 to about lxl012 colony forming units (cfu) per gram formulation.” Therefore, it would have been obvious with reasonable expectation of success to a POSITA at the time of filing of the instant application to combine the teachings Wolfs, Ochoa-Cortes, Russell, PubChem CID 4628, Shapera, Sylvester and Aceti to develop a composition comprises Bifidobacterium to arrive at the claimed invention, because probiotic exerts beneficial effects on the health of the host by suppressing inflammation.
Claims 44 is rejected under 35 U.S.C. 103 as being unpatentable over Wolfs, PubChem CID 4628, Ochoa-Cortes, Ban, Ribner, Shapera and Sylvester as applied to claims 28 above, in view of Li et al. (The Kaohsiung J. Med. Sc., 34(3), 134–141).
Regarding claim 44, the combined teachings of Wolfs, PubChem CID 4628, Ochoa-Cortes, Ban, Ribner, Shapera and Sylvester does not explicitly teach administration of BDNF.
However, Li (abstract; page 135) teaches BDNF plays significant role in preserving intestinal mucosal barrier function, inhibiting cell death during inflammation which alters the gut microbiota. For example, Li (page 135; page 137-140) teaches reduced BNDF expression have a significantly damaged intestinal barrier lead to disruption of the colonic epithelial barrier, compared with normal BDNF expression. Given that NEC is characterize by intestinal barrier breakdown, thus, a POSITA would have recognized that administering BDNF would support epithelial barrier integrity but also restores microbial balance, which is the therapeutic goals in NEC management. Furthermore, a POSITA would have also considered using BDNF in a composition to treat or prevent NEC. This is because Wolfs discloses that NEC is characterized by inflammation and damage to the intestinal mucosa, similar to the gut inflammation studied by Li which demonstrated that BDNF has anti-inflammatory properties and preserved intestinal mucosal barrier function.
Claims 45-46 is rejected under 35 U.S.C. 103 as being unpatentable over Wolfs, PubChem CID 4628, Ochoa-Cortes, Ban, Ribner, Shapera and Sylvester as applied to claims 28 above, in view of EMA (https://www.ema.europa.eu/en/documents/mrl-report/oxolinic-acid-extension-bovine-summary-report-4-committee-veterinary-medicinal-products_en.pdf) (2003).
Regarding claim 45-46, as applied above to claims 28, 34, 46-47, EMA (page 2) teaches an orally administered microbiologically acceptable daily intake (ADI) of 2.5 mg/kg bw (i.e. 150 mg/person) was previously established for oxolinic acid. Therefore, it would have been obvious to a POSITA to administer oxolonic acid at 2.5 mg/kg which falls within the range of the claimed invention to treat NEC, because NEC is often exacerbate by bacteria infection, especially in premature infants.
Response to Argument
Applicant argues that the claimed invention demonstrates unexpected and improved properties not found in the prior art. For example, “glial-activating compounds” such as oxolinic acid are shown to induce BDNF release from enteric glial cells, thereby helping to prevent NEC. Applicant’s argument is not persuasive because NEC belongs to within the broader category of enterocolitis and gastrointestinal inflammatory disease; and given oxolinic acid is known in the art to treat acute enterocolitis, gastrointestinal infection, and targets similar bacterial strains to those contributing to NEC pathology; it would have been obvious to a POSITA with a reasonable expectation of success to consider the use of oxolinic acid for treating NEC as an obvious application within the same disease family.
Furthermore, Applicant’s assertion of unexpected results based on oxolinic acid inducing BDNF expression in enteric glial cells does not overcome the prima facie case of obviousness. It is important to note that the prior art already teaches oxolinic acid for treating acute enterocolitis and gastrointestinal infections, condition closely related to NEC. Given NEC is a severe form of enterocolitis involving bacterial infection and inflammation, similar therapeutic effects would have been expected. Therefore, discovering a new mechanism of action for a known compound used for the same obvious purpose does not render the claimed use nonobvious. In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990). See MPEP 2145.
Applicant’s argument that none of the individual references teaches all of the claim limitations such as treating NEC with oxolinic acid, is not persuasive because a rejection under 103 is based on the combined teachings of the prior art, thus one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Furthermore, although the combined references do not explicitly disclose treating NEC with oxolinic acid, but an explicit teaching is not required to establish obviousness. Further note, and as indicated above, oxolinic acid is known in the art to treat acute enterocolitis, gastrointestinal infection and the newly added prior art such as, Sylvester clearly teaches that NEC is associated with infection or colonization by Gram-negative enteric organisms, including E. coli, Klebsiella species, Proteus species, Staphylococcus species, Enterobacter species and enterococci. Sylvester also discloses NEC management includes antibiotic therapy directed towards bacterial pathogens. Additionally, Shapera discloses antibacterial activity of oxolinic acid against same Gram-negative organism, including E. coli, Klebsiella, Proteus, Enterobacter, and had been administered therapeutically in pediatric patients. Therefore, a POSITA would have been motivated to evaluate oxolinic acid as an antibacterial treatment option for NEC associated bacterial infections, with a reasonable expectation of success that such approach would inhibit the bacterial pathogens implicated in NEC. Therefore, the rejection is maintained.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PIERRE PAUL ELENISTE whose telephone number is (571)270-0589. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JAMES H ALSTRUM-ACEVEDO can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/P.P.E./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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