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 with traverse of Group II in the reply filed on 12/6/24 was previously acknowledged.
In the reply filed 6/18/25, Applicants canceled claim 19 and amended claim 17.
Claims 1-17 and 20-30 are pending.
Claims 1-16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim.
Claims 17 and 20-30 read on Group II and are consideration.
Claim Rejections -Withdrawn
The rejection of claims 17 and 19-30 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph is withdrawn due to amendment of claim 17 to oral mucositis.
The rejection of claims 17, 19-20, 24, 27-30 under 35 U.S.C. 103 as being unpatentable over Stubberfield et al. (“Glutamine as a Neuroprotective Agent in High-dose Paclitaxel-induced Peripheral Neuropathy: A clinical and Electrophysiological Study” Clinical Oncology (2005) 17: 271-276) in view of Roth (“Nonnutrive effects of Glutamine”; The Journal of Nutrition; vol 138(10) Oct. 2008; 2025S-2013S) is withdrawn due to amendment of claim 17 to oral mucositis.
Claim Rejections - 35 USC § 103-Modified
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 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.
Claims 17 and 20-30 are rejected under 35 U.S.C. 103 as being unpatentable over in view of Cerchietti et al. (“Double-Blinded, placebo-controlled trial on intravenous L-Alanyl-L-Glutamine in the incidence of oral mucositis following chemoradiotherapy in patients with head and neck cancer”; Int. J. Radiation Oncology Biol. Phys, Vol. 65 (5), pp. 1330-1337, 2006) in view of Carneiro-Filho et al. (“Alanyl-Glutamine Hastens Morphologic Recovery From 5-Fluorouracil-Induced Mucositis in Mice”; Nutrition 20: 934-941, 2004) as evidenced by the CDC-National Center for Health Statistics (accessed 9/18/25).
Cerchietti et al. teach head and neck cancer is the fifth most common cancer worldwide and treatment of advanced cancer has improved dramatically during the past decade allowing a discussion of cure rate in many patients (p, 1330, 1st col., 1st para.). Cerchietti et al. teach chemo-radiotherapy (CRT) has established itself as a central treatment modality either upfront as definitive therapy or an adjuvant to surgery (p. 1330, bottom of 1st col. to top of 2nd col.). Cerchietti et al. teach almost 100% of patients treated with CRT suffer clinically significant mucositis and more than 40% of these can be severe (p. 1331, top of 1st col.). Cerchietti et al. teach that patients with head and neck cancer are naturally depleted or glutamine, a condition that is further exacerbated by the effects of cancer treatment (p. 1331, 1st col., 2nd para.). Cerchietti et al. teach an effective way to supplement glutamine to head and neck cancer patients could be intravenous administration of the dipeptide, alanyl-glutamine which is a stable glutamine derivative that has been shown to be useful in decreasing 5-FU induced mucositis (p. 1331, 1st col, bottom of 2nd para.). Fig. 1 teaches the schedule of antineoplastic and intervention treatments (the down arrow indicates the timing of alanyl-glutamine administration) (p. 1332). Cerchietti et al. teach that thirty two patients scheduled for treatment with CRT for head and neck cancer with a high possibility of developing severe oral mucositis were asked to participate in the trial (p. 1332, bottom of 2nd col.). Cerchietti et al. teach of the 29 patients included in the study, 14 received alanyl-glutamine and 15 received placebo (p. 1333, 1st col., 2nd para). Cerchietti et al. teach a significant difference in the intensity of mucositis developed in patients receiving placebo compared with alanyl-glutamine (p. 1333, 1st col., 1st para.). Cerchietti et al. teach the number of patients with severe objective mucositis and the number of patients with WHO Grade 4 were significantly higher in the placebo group compared in the treatment group (p. 1333, bottom of 1st col. continued to 2nd col.).
Cerchietti et al. does not teach the alanyl-glutamine teach is formulated for oral administration or the dose of the alanyl-glutamine. However, the teachings of Carneiro-Filho et al. cure this deficiency.
Carneiro-Filho et al. teach the deleterious effects of chemotherapy drugs in gastrointestinal epithelium have been well documented. Carneiro-Filho et al. teach approximately 60% of the patients with colon cancer receiving 5-FU develop oral ulcers or GI symptoms secondary to chemotherapy (p. 934, 2nd col.,).
Carneiro-Filho et al. teach administration of the Gln derivative (Ala-Gln) orally can be even more effective and feasible than Gln for speeding intestinal morphologic recovery by its chemical stability and solubility properties (p. 934, last para. of Introduction). Carneiro-Filho et al. teach alanyl-glutamine was diluted in PBS and given orally by gavage starting 3 days before the 5-FU administration and continued throughout the experimental course (p. 935, 1st col, “Treatment Regimens” para.). Carneiro-Filho et al. teach that oral alanyl-glutamine supplementation demonstrated a great potential to ameliorate the 5-FU induced intestinal mucosal injury by accelerating the intestinal epithelium recovery (p. 940, 1st col., 4th para.). Carneiro-Filho et al. teach although the finding are encouraging regarding the potential use of oral alanyl-glutamine in adjuvant therapies for patients undergoing cancer chemotherapy, additional studies using more quantitative methods are needed to confirm these results in humans (p. 940, 1st col., 5th para.).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the invention to administer the alanyl-glutamine orally as taught by Carneiro-Filho et al. to a human patient for treatment of oral mucositis. A person would be motivated to administer the dipeptide orally because Carneiro-Filho et al. teach administration of the Gln derivative (Ala-Gln) orally can be even more effective and feasible than glutamine for speeding intestinal morphologic recovery by its chemical stability and solubility properties. There is a reasonable expectation of success given that Carneiro-Filho et al. teach oral alanyl-glutamine supplementation demonstrated a great potential to ameliorate the 5-FU induced intestinal mucosal injury by accelerating the intestinal epithelium recovery and stated that although the finding are encouraging regarding the potential use of oral alanyl-glutamine in adjuvant therapies for patients undergoing cancer chemotherapy.
Furthermore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the invention to try the dipeptide of alanyl-glutamine for treatment of oral mucositis in a patient suffering from oral mucositis. MPEP 2143 states: Exemplary rationales that may support a conclusion of obviousness include “Obvious to try” – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success to reject a claim based on this rationale, Office personnel must resolve the Graham factual inquiries. Then, Office personnel must articulate the following:
(1) a finding that at the time of the invention, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success; and
(4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness.
In the instant case, there is a recognized need for the treatment of oral mucositis. Cerchietti et al. teach that there is a high likelihood of developing clinically significant mucositis with CRT (p. 1330, bottom of 2nd col.). Cerchietti et al. teach that providing glutamine during cancer treatment has the potential to abrogate treatment related toxicity (p. 1331, 1st col, 2nd para.). Therefore, there is a need for prevention and treatment of oral mucositis in response to CRT. At the time of the invention there had been a finite number of identified, predictable potential solutions for the recognized problem, including administering the dipeptide alanyl-glutamine. One of ordinary skill in the art at the time of the effective filing date of the invention would be motivated to try alanyl-glutamine for treatment of a patient undergoing CRT suffering from oral mucositis. A person of ordinary skill in the art would look to the teachings of Cerchietti et al. and Carneiro-Filho et al. that teach administering the dipeptide reduced the severity of mucositis and be justified in administering it to a patient suffering from the cancer treatment side effect. There is a reasonable expectation of success given that both Cerchietti et al. and Carneiro-Filho et al. teach the dipeptide was effective orally and intravenously for reducing the severity of oral mucositis.
With respect to the new limitation “about 30-75 grams over the course of one day in one or multiple administration” and claims 28-29, the dose and timing of the active agent for treating or preventing a disease or disorder is a result-effective variable and the determination of the optimum or workable ranges of said variable maybe characterized by routine experimentation (Please see MPEP 2144 II-Optimization of Ranges). In the instant case, Cerchietti et al. teach patients received 300 or 400 mg/kg body weight of intravenous alanyl glutamine (p. 1331, bottom of 1st col.). The CDC teaches the average weight of an adult male is 199 lb (90.265 kg). Administering 300-400 mg/kg to a man weighing an average of 90.265 kg is 27-36 g. It would have been obvious and routine experimentation to a person of ordinary skill in the art with a reasonable expectation of success to optimize the dose and number of times administering the drug to arrive at the dose range and administration times of claims 17 and 28-29. Please note that MPEP 2131.01 states: that an extra reference or evidence can be used to show an inherent characteristic of the thing taught by the primary reference. In the instant case, the CDC reference is relied upon only to establish the average weight of a man.
The new limitation “zinc is optionally co-administered with the Alanyl-Glutamine” is interpreted as completely optional and not a required element of claim 17.
With respect to claims 20-21, Cerchietti et al. et al. teach oral mucositis is caused by CRT (p. 1330, 1st col, 1st para.; Fig. 1). CRT is chemo-radiotherapy, meeting the limitation of the cancer treatment side effect is caused by chemotherapy and radiation. -
With respect to claims 22-23, Carniero-Filho et al. teach the dipeptide is administered 3 days before administration of 5-FU (p. 935, 1st col., “Treatment regimen” para.), meeting the limitation of “..Composition administered-…3 days prior to initiation of a cancer treatment regimen”.
With respect to claim 24, Fig. 1 discloses the schedule of antineoplastic and intervention regimen (p. 1332). Cerchietti et al. teach the dipeptide is administered on days 1-5, 21-25, 35, 42, 49 and 56 (down arrows in Fig. 1). Cisplatin treatment started on day 1, therefore administration of the dipeptide on days 2-5, 21-25, 35, 42, 49 and 56 meets the limitation of “after initiation of a cancer treatment of a subject”.
With respect to claim 25, Fig. 1 discloses the schedule of antineoplastic and intervention regimen (p. 1332). Cerchietti et al. teach the dipeptide is administered on days 1-5, 21-25, 35, 42, 49 and 56 (down arrows in Fig. 1). Administration of the dipeptide at day 21 meets the limitation of “…3 weeks….of 21 days after a cancer treatment regimen”.
With respect to claim 26, Fig. 1 discloses that the dipeptide is administered concurrently with administration of the cancer treatment of a subject.
With respect to claim 27, Cerchietti et al. teach the dipeptide was administered once daily to the subject (p. 1332, 1st col, “Intervention treatment” para.).
With respect to claim 30, and the limitation “wherein said administration results in a higher plasma glutamine concentration than that observed following oral administration of an equivalent dose of glutamine”, the references of Cerchietti et al. and Carniero-Filho et al. make obvious the administration of oral alanyl-glutamine for treatment of the cancer treatment side effect of oral mucositis. Therefore, the oral solution of alanyl-glutamine made obvious by the combined references above would inherently have all of the activities and properties of the method of claim 17. The MPEP § 2112 states: “Once a reference teaching product appearing to be substantially identical is made the basis of a rejection, and the Examiner presents evidence or reasoning tending to show inherency, the burden shifts to the Applicant to show an unobvious difference ‘[t]he PTO can require an Applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his [or her] claimed product. Whether the rejection is based on inherency’ under 35 U.S.C. 102, on prima facie obviousness’ under 35 U.S.C. 103, jointly or alternatively, the burden of proof is the same…[footnote omitted].” The burden of proof is similar to that required with respect to product-by-process claims. In re Fitzqerald, 619 F.2d 67, 70, 205 USPQ 594, 596 (CCPA 1980) (quoting In re Best, 562 F.2d 1252, 1255, 195 USPQ 430,433- 34 (CCPA 1977)).” In other words, Cerchietti et al. and Carniero-Filho et al. make obvious administering the same composition (oral alanyl-glutamine) to the same patient population (a patient suffering from a cancer treatment side effect). Therefore, the same composition administered to the same patient population would result in a higher plasma glutamine concentration.
Response to Arguments
Applicant's arguments filed 6/18/25 have been fully considered but they are not persuasive. Applicants argue that claim 17 has been amended to require 30-75 grams of oral alanyl-glutamine. Applicants argue that Cerchietti is drawn to intravenous administration of alanyl-glutamine and fails to suggest oral administration. Applicants argue that various bioavailability factors may govern oral drug absorption vs intravenous administration including drug solubility, mucosal permeability, stability and GI tract environment may affect dosing. Although the secondary reference may disclose oral administration of alanyl-glutamine but is directed to studies of intestinal mucositis in mice and not oral mucositis as required by the claim.
These arguments were considered but are not persuasive because 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). In the instant case, administration of alanyl-glutamine for treatment of oral mucositis as a side effect of cancer treatment is well known in the art. The Examiner agrees that Cerchietti does not teach the claimed dose, however Carniero-Filho reference is used to make obvious oral administration. The primary reference of Cerchietti teach treatment of oral mucositis. As indicated above, the dose and dose intervals are result driven variables and it would have been obvious to optimize the dose and how often it is administered. MPEP 2144.05 II A states: Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” Applicants are invited to show evidence that the concentration is critical.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
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/T.L.M/Examiner, Art Unit 1654
/SUDHAKAR KATAKAM/Primary Examiner, Art Unit 1658