DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 09/17/2025 has been entered.
3. Claims 69, 79, 81-82, 88-89, and 100-111 are pending.
4. Claims 104-107 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.
5. Claims 69, 79, 81, 82, 87-89, 100-103 and 108-111 are under examination as they read on a method for treating inflammatory bowel disease (IBD) in a pediatric patient, comprising intravenously administering an antibody that has binding specificity for human α4β7 integrin comprising SEQ ID NOs: 4-9 and the species of (i) 200 mg dose schedule of 0, 2, 6 weeks and intravenous administration, (ii) ulcerative colitis, (iii) a patient weighing less than 30 kg, (iv) patient who had a lack of an adequate response with , lost response to, or was intolerant to a TNFα antagonist.
6. Applicant’s IDS, filed 9/17/2025, is acknowledged.
7. 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.
8. Claims 69, 79, 81, 82, 87-89, 100-103 and 108-111 are rejected under 35 U.S.C. 103 as being unpatentable over Singh et al (Inflamm Bowel Dis. Sept. 2016;22:2121–2126, IDS #9) in view of 125476Orig1s000 (Approval Package, page 1-18, May 20, 2014, of record) or WO2016105572 (IDS) and US 20140341885 or WO/2017/165778, as is evidenced by the specification on page 15, 2nd ¶).
Singh et al teaches that vedolizumab is efficacious and safe in pediatric IBD patients, with UC (with proximal to the rectum inflammation, since all UC types have proximal to the rectum inflammation) patients experiencing earlier and higher rates of remission than CD patients (abstract). Singh teaches that the age at start of vedolizumab for UC is 7-17 years (overlapping with claimed 2-10 years old) and have PUCAI score between 10-55 (overlapping with ≥ 35) and by definition moderately active UC. After, 14 weeks of vedolizumab treatment the PUCAI score decrease form 10-55 to 0-10 (see Table 2, under UC, PUCAI). Singh also teaches that all patients received vedolizumab intravenously at 0, 2, and 6 weeks and then approximately every 8 weeks. The dose of vedolizumab was 300 mg in 39 patients (75%) and dosed by weight in smaller patients—6 mg/kg in 11 patients and 5 mg/kg in 2 patients. Forty patients (77%) remain on vedolizumab at the time of last follow-up, with median follow-up time of 22 (range 6–70) weeks (page 2123, left col., top ¶). Standard dosing in adult vedolizumab patients is 300 mg per infusion, and no specific guidelines exist for pediatric dosing. Pediatric patients, many of them smaller in size and weight, may require an individualized dose. Although 75% of our patients received the standard dosing, most others received 6 mg/kg up to a maximum of 300 mg. This 5 to 6 mg/kg dose was derived by using an average adult weight of 50 to 60 kg and extrapolating a weight-based dosing from the standard adult dose of 300 mg (page 2124, right col., 4th ¶). No difference in remission rates at any time points was noted in patients receiving 300 mg compared with weight-based dosing. A recent study showed improvement in mean disease activity scores with an increase in vedolizumab frequency to every 4 weeks from every 8 weeks dosing, without any increase in adverse events (page 2124, right col., 5th ¶). Singh explicitly suggests investigating factors affecting vedolizumab clearance and subsequent ideal dosing in pediatric patients (see page 2125, left col, top ¶). Singh teaches that the lack of standardized dosing for pediatric patients led to variation of dosing in this study, which introduces this as a potentially confounding factor.
The reference teachings differ from the claimed invention only in the recitation of 200 mg in claims 69, 79, 81-82, 88.
125476Orig1s000 required the following studies: Conduct a dose-ranging study to determine the pharmacokinetics/ pharmacodynamics, safety, and tolerability of Entyvio (vedolizumab) in pediatric patients 5 to 17 years of age with moderately to severely active ulcerative colitis who have failed conventional therapy. Conduct a randomized, placebo-controlled, blinded, multicenter study of the induction and maintenance of clinical response and remission by vedolizumab in pediatric patients 5 through 17 years with moderately to severely active ulcerative colitis who have failed conventional therapy (see page 4, under section 1.4).
The `752 publication teaches a vedolizumab population pharmacokinetic model, NONMEM 7, was developed using the first-order conditional estimation with η-ε interaction (FOCEI) method and extensively sampled phase 1 and 2 data (see the entire document, page 47, lines 20+ and page 49, lines 12+). The objectives were to (1) characterize the pharmacokinetics of vedolizumab in patients who received repeated IV infusion of vedolizumab 300 mg for up to 52 weeks; (2) identify clinically relevant determinants of vedolizumab clearance in patients; and (3) describe the pharmacokinetic-pharmacodynamic relationship of vedolizumab in patients using MAdCAM-1 as the pharmcodynamic endpoint (see page 42, under Example 1). The `752 publication teaches that the study population consisted of 2554 individuals who contributed 18427 evaluable vedolizumab serum samples, including 87 healthy volunteers from the phase 1 study, 46 patients from the phase 2 study (UC), and 891, 1115, and 415 patients from the phase 3 GEMINI 1 (UC), GEMINI 2 (CD), and GEMINI 3 (CD) studies, respectively. Demographics and other characteristics of the pharmacokinetic analysis population are summarized in Table 1. The analysis population consisted of 1290 men and 1264 women with ages ranging from 18 to 78 years and baseline body weights ranging from 28 to 170 kg. A total of 1530 individuals had CD and 937 had UC; 87 were healthy volunteers ( see page 49, under Pharmacokinetic Analysis Population). The `752 publication teaches that vedolizumab is administered at a dose of 50 mg, 100 mg, 180 mg, 300 mg, or 600 mg (see page 29, line 20). The `752 publication teaches that the vedolizumab is administered at 0, 2 and 6 (induction) weeks and every four weeks or every eight weeks thereafter (maintenance) (i.e., 0, 2, 6, every 8 (i.e., 14 wks after 1st dose) weeks) (see page 29-30, bridging ¶, see published claims 34-35, 45-52). The `572 publication teaches and claims that methods of treating a human patient suffering from Inflammatory Bowel Disease (IBD) including ulcerative colitis with 300 mg vedolizumab, wherein the patient has an inadequate response with, lost response to or was intolerant to a TNF blocker (see claims 53-59). The `572 publication teaches that Vedolizumab is indicated for the treatment of patients with moderately (PUCAI score of 35-64) to severely (PUCAI score of 65-85) active ulcerative colitis (UC) (see page 14, lines 13+, page 42, lines 13+). Vedolizumab is an integrin receptor antagonist indicated for adult patients with moderately to severely active UC or CD who have had an inadequate response with, lost response to, or were intolerant to a tumor necrosis factor (TNF) blocker or immunomodulator, or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids (page 24, lines 19+). The `572 teaches that vedolizumab is and IgG1 antibody (see pages 1-2, bridging ¶; page 59, lines 9+, page 24, top ¶). The human patient or subject may be a child (page 22, lines 18-20).
The `885 publication teaches that methods of treating human patient suffering from IBD such as moderate to severely ulcerative colitis [0174] with a humanized immunoglobulin having binding specificity for human α4β7 integrin, the humanized immunoglobulin, vedolizumab, is administered in a final dosage of 200 mg (see claims 24-26, 29-30, 34-35, 53, [0037], [0141], [0142]). The formulation of the invention can be for subcutaneous, intravenous [0022]. The human subject may be a child [0166].
Given that the vedolizumab treats ulcerative colitis of patients of 7-17 years old having body weight of 18-28 kg which is outside the measured baseline body weights range measured by the `572 publication and that Singh shows that doses between 6 mg/kg up to maximum 300 mg are effective for treating pediatric ulcerative colitis patient, those skilled in the art would found it obvious to use the population model taught by the `572 publication to determine the fixed dosing with vedolizumab in the treatment of pediatric patients with moderately to severely active UC who have a body weight of less than 30 kg taught by Singh et al by determine the pharmacokinetic analysis population model taught by the `572 publication for the patients having less than 30 kg body weight which would result in a fixed dose of 200 mg dose as taught by the `885 publication.
The `778 publication teaches and claims methods of treating a gastrointestinal immune-related adverse event (gi-irAE) in a mammalian subject undergoing an immune oncology treatment, comprising administering a therapeutically effective amount of a polypeptide that inhibits MAdCAM- α4β7 integrin binding to the subject, wherein the polypeptide that inhibits MAdCAM- α4β7 integrin binding is an anti-α4β7 integrin antibody and is administered at a unit dose of about: 200 mg to a human subject (see claims). The `778 vedolizumab is administered at a dose of 50 mg, 100 mg, 108 mg, 165 mg, 200mg, 216mg, 300 mg, 450 mg, 500 mg, or more. 200, 300, or 450 mg vedolizumab may be administered by intravenous infusion at zero, two, and six weeks, and then at four weeks intervals or eight week intervals thereafter. In some embodiments, 200, 300, or 450 mg vedolizumab may be administered by intravenous infusion at zero, two, and six weeks, and then at two, three or four week intervals [0065]. The `778 publication teaches that the polypeptide that inhibits MAdCAM- α4β7 integrin binding is administered at least four times, where the second dose is administered about two weeks after the first administration, the third dose is administered about four weeks after the first administration, and the fourth dose is administered about 12 weeks after the first administration [0010]. The `778 publication teaches subjects treated by the methods exhibit reduced, no grade 3 or 4 (no: Grade 3 colitis, Grade 4 (or Grade 3 that persists or worsens over 3-5 days) colitis or diarrhea), only grade 1-2 diarrhea, or if any grade 2 occurs, that the symptoms resolve, e.g., by symptomatic antidiarrheal treatment without adding prednisone or anti-TNF-α treatment [0069]. It is noted that moderate PUCAI score of 35-64)/ severely (PUCAI score of 65-85) colitis (Grade 2 and above). The `778 publication teaches that the treatment exhibits reducing or eliminating the use of: corticosteroids ( oral or systemic), antibiotics ( oral or parenteral), non-corticosteroid immunosuppressive medication (e.g. anti-TNF-α agents), lower endoscopy, hospitalizations, or a combination thereof [0017].
Given that the vedolizumab treats ulcerative colitis of patients of 7-17 years old. The overlapping age range between Singh and the claimed invention is 7-10 years with a body wight of 23kg to 30 kg which is outside the measured baseline body weights range measured by the `572 publication and that Singh shows that doses between 6 mg/kg (i.e, 138mg to 180mg) up to maximum 300 mg are effective for treating pediatric ulcerative colitis patient, those skilled in the art would be motivate to use a low dose of vedolizumab such as 200 mg taught by the `778 publication in the treatment of a pediatric patient with moderately active ulcerative colitis taught by Singh.
The teachings of Singh pertaining to the lack of standardized dosing for pediatric patients led to variation of dosing and the 125476Orig1s000 explicitly required conducting a dose-ranging study to determine the pharmacokinetics/ pharmacodynamics, safety, and tolerability of Entyvio (vedolizumab) in pediatric patients 7 to 17 years of age with moderately to severely active ulcerative colitis who have failed conventional therapy and the teachings of `752 publication indicating success in determining vedolizumab fixed dosing in patient with UC using vedolizumab population pharmacokinetic model in the face of having to solve a similar problem would have led one of ordinary skill in the art at the time the invention was made to combine the references to solve a well-known problem in the art, optimize dosing regimens. The strongest rationale for combining reference is a recognition, expressly or implicitly 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 In re Sernaker 17 USPQ 1, 5-6 (Fed. Cir. 1983) see MPEP 2144. Furthermore, in KSR Int'l Co. v. Teleflex Inc., 550 U.S. m, 2007 WL 1237837, at "13 (2007) it was stated that "if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond his or her skill".
A person having ordinary skill in the art would have found it obvious to determine the optimum pediatric patient doses of VDZ that enhances anti-UC effect of result-effective variables known in the art. Recognition that a property (VDZ treatment results in UC remission) is affected by the variable (age/weight of the patient) is sufficient to find the variable result-effective. The Board stated that "all that remained to be achieved over the prior art was the determination that a specific dose within a previously suggested dose range, and its corresponding dosing schedule, would have been safe and effective for the treatment of human patients." Genzyme Therapeutic Prods. v. Biomarin Pharms., No. 2015-1720.
"[I]t is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456 (CCPA 1955); see also In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003). "Only if the 'results of optimizing a variable' are 'unexpectedly good' can a patent be obtained for the claimed critical range." In re Geisler, 116 F.3d 1465, 1469 (Fed. Cir. 1997) (quoting In re Antonie, 559 F.2d 618, 620 (CCPA 1977)). "[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272, 276 (CCPA 1980).
The functions recited in the wherein clause flow naturally from the teachings of the prior art. Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985 (“The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.”), and Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347 (Fed. Cir. 1999) (“[T]he discovery of... a scientific explanation for the prior art's functioning, does not render the old composition patentably new to the discoverer.”)). Here, the recited functional outcome would naturally and necessarily flow from inhibition of α4ß7 by administering Vedolizumab. Accordingly, the prior art teaches the same method, the product used in the reference method are the same as the claimed method. Therefore, the claimed functional outcome would naturally and necessarily flow from inhibition of α4ß7 with the Vedolizumab in treating pediatric colitis in a human subject. Moreover, Shen et al teach that UC cohorts stratified by age at diagnosis (> 30 years vs < 30 years) showed no statistically significant difference in clinical response or remission.
The specification on page 15, 2nd discloses that PUCAI score 35 to 64 moderate disease and 65 to 85 severe disease.
Claims 110-111 are included because it would have been obvious to target pediatric patient has very early onset UC (onset <6 years of age) having weights 10 Kg to less than 30kg and PUCAI score of at least 30 because vedolizumab is efficacious and safe in pediatric UC patients experiencing earlier and higher rates of remission for those at age 7-17. Further, 14 weeks of vedolizumab treatment of pediatric patient resulted in the PUCAI score decrease form 10-55 to 0-10. Singh demonstrates it was known the claimed vedolizumab could be used to treat UC pediatric patient.
It is noted that “rectal bleeding subscore of ≥ 1 point or absolute rectal bleeding subscore of ≤ 1 1 point” is a key component of overall of Mayo score, wherein “rectal bleeding subscore of ≥ 1 point” ranges from 1-3 which score of 1 is visible blood with stool less than half the time and score of 3 passing blood alone. Similiarly the “absolute” score in clinical trials for “clinical response” is rectal bleeding score of 0 or 1 (the claim encompasses all clinical responses).
Mayo Score Calculation formula: sum of the scores of the four parameters. Clinical response is defined as a decrease of at least 3 points and at least 30% versus baseline, which must include a decrease in the score for rectal bleeding of at least 1 point, or an absolute score for rectal bleeding not exceeding 1.
A Mayo score of ≥ 3 indicates mild to moderate or severe activity, depending on the total score. Specifically, a score between 3 and 5 points signifies mild activity, while scores from 6 to 10 point to moderate activity, and a score of 11 or more is considered severe activity. The score is base on the four parameters: stool frequency, rectal bleeding, mucosal appearance via endoscopy and physician’s global assessment.
With respect to recited results achieved “wherein the pediatric patient achieves a clinical response defined as a reduction in complete Mayo score of ≥3 points and ≥30% from a baseline and a decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤ 1 point, and achieves clinical remission with a Pediatric UC Activity Index (PUCAI) score of less than 10 at 14 weeks after the initial dose” flow naturally from the teachings of the prior art. The functions recited in the wherein clause flow naturally from the teachings of the prior art. Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985 (“The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.”), and Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347 (Fed. Cir. 1999) (“[T]he discovery of... a scientific explanation for the prior art's functioning, does not render the old composition patentably new to the discoverer.”)). Here, the recited functional outcome would naturally and necessarily flow from inhibition of α4ß7 by administering Vedolizumab. Accordingly, the prior art teaches the same method, the product used in the reference method are the same as the claimed method. Therefore, the claimed functional outcome would naturally and necessarily flow from inhibition of α4ß7 with the Vedolizumab in treating moderately to severely active ulcerative colitis in a pediatric patient.
None of the recited steps differs in any material way from the process disclosed in Singh (in view of secondary references). And there is no evidence that the claimed “patient achieves a clinical response defined . . .“ would have been unexpected or unattainable from the process disclosed in Singh. In fact, there is no evidence that the process disclosed in Singh did not produce "a clinical response defined as a reduction in complete Mayo score of ≥3 points and ≥30% from a baseline and a decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point, and achieves clinical remission with a Pediatric UC Activity Index (PUCAI) score of less than 10 at 14 weeks after the initial dose”. The court has held that where "all process limitations ... are expressly disclosed by [the prior art reference], except for the functionally expressed [limitation at issue]," the PTO can require an applicant "to prove that the subject matter shown to be in the prior art does not possess the characteristic relied on." In re Best, 562 F.2d 1252, 1254-55 (CCPA 1977). The court noted that "[w]hether the rejection is based on `inherency' under 35 U.S.C. § 102, [or] on `prima facie obviousness' under 35 U.S.C. § 103,... the burden of proof is the same." Id.
Simply because Singh never quantified the clinical response achieved by its disclosed embodiments does not preclude the possibility, or even likelihood, that its process achieved "a clinical response defined as a reduction in complete Mayo score of ≥3 points and ≥30% from a baseline and a decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point, and achieves clinical remission with a Pediatric UC Activity Index (PUCAI) score of less than 10 at 14 weeks after the initial dose”. In the absence of any evidence that the claimed clinical response would have been expected in light of the Singh disclosure, there is no indication that the limitation is anything other than mere quantification of the results of a known process.
Where “‘all process limitations . . . are expressly disclosed by [the prior art reference], except for the functionally expressed [limitation at issue],’ the PTO can require an applicant ‘to prove that the subject matter shown to be in the prior art does not possess the characteristic relied on.’” Southwire (Fed. Cir. 09/08/17) (aff’g PTAB obviousness decision; “mere quantification of the results of a known process” is not patentable).
From the combined 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. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Applicant’s arguments, filed 09/17/2025, have been fully considered, but have not been found convincing.
Applicant submits that Singh et al does not teach or suggest a 200 mg dose, as claimed. Also, Singh et al does not teach the claimed patient who is 2 to 10 years old and weights 10 kg to less than 30 kg. Table 1 of Singh et al only describes patients 7-17 years old (median of 14.3 years old) and does not provide any information regarding weight-Singh et al merely teaches that the “dose of vedolizumab was 300 mg in 39 patients (75%) and dosed by weight in smaller patients -6mg/kg in 11 patients and 5 mg/kg in 2 patients” (see page 2123, left col., first para.). Notably, a 5-6 mg/kg dose equates to a 50-60 mg dose for a claimed smaller patient who weights 10 kg, which is far below the claimed fixed 200 dose that Applicant has shown to be both effective and safe. Moreover, Singh et al is silent regarding a complete Mayo score and/or a rectal bleeding subscore. Applicant concluded that one of ordinary skill would not predict nor have an expectation of success from the teachings of Singh et al that a 200 mg dose would be “efficacious and safe” in a patient who is 2-10 years old and weights 10 kg to less than 30 kg, as alleged by the Office, let alone achieve a clinical response defined as a reduction in complete Mayo score of ≥3 point and ≥30% from a baseline and a decrease in rectal bleeding subscore of ≥1 [pomt or absolute rectal bleeding subscore of ≤1point at 14 weeks after starting treatment.
Applicant points that the Office cites to 1254760rigs000, the '572 publication, the '885 publication, and the '778 publication to allege that a skilled artisan would arrive at a 200 mg dose. However, given that Singh et al. describes "clinical remission at week 14 defined as PUCAI<10 or wPCDAI<12.5" (see page 2122, "Outcomes") using the 5-6 mg/kg doses described therein, one of ordinary skill would not be motivated by the teachings of Singh et al. alone or in combination with 1254760rig1s000, the '572 publication, the '885 publication, and the '778 publication to adjust the dose for the claimed pediatric patient who is 2 to 10 years old and weighs 10 kg to 30 kg to a 200 mg dose in order to achieve the claimed clinical response (e.g., increase a 50-60 mg dose to 200 mg for a claimed patient who weighs 10 kg).
This is not found persuasive because Applicant present no compelling evidence of secondary indicia of non-obviousness to rebut the Examiner’s prima facie case of obviousness. There is no evidence that the optimization of the single unit dosage was anything but routine and it is well settled that arguments of consul cannot take the place of factually supported objective evidence. The experimentation needed to arrive at the subject matter claimed was “nothing more than routine” application of a well-known problem-solving strategy, we must conclude it is not invention. Pfizer, Inc. v. Apotex, Inc., 480 f.3d 1348, 1368 (fed. Cir. 2007). The issue here is the selection of a dosing regimen, i.e., 200 mg fix dosing, from among the 5-6 mg/kg up to maximum of 300 mg dose for patients age 7-17 years old (for 10 kg subject, the dose range is 50-300mg). A 200 mg single unit dosage would be obvious over effective working examples requiring therapeutic dosages that that provide remission rates at any time points was noted in patients receiving 300 mg compared with weight-based dosing (i.e., for 10-30 kg subject, the dose range is 50-60mg -150-180mg). Singh et al teach that no difference in remission rates at any time points was noted in patients receiving 300 mg compared with weight-based dosing.(see page 2124, right col., last ¶). Importantly, Singh teaches that no specific guidelines exist for pediatric dosing and pediatric patients with smaller in size and weight may require an individualized dose would motivate those skilled in the art to select a specific vedolizumab pediatric dosing using population pharmacokinetic model, NONMEM 7 taught by the `752 publication.
Applicant submits that 1254760rig1s000 is an approval letter for Entyvio dated May 20, 2014 from the Center for Drug Evaluation and Research (see page 1). The Office cites 1254760rig1s000 for allegedly describing "a randomized, placebo-controlled, blinded, multicenter study of the induction and maintenance of clinical response and remission by vedolizumab in pediatric patients 5 through 17 years with moderately to severely active ulcerative colitis who have failed conventional therapy" (see page 3, third para. of the Office Action). However, 1254760rig1s000 merely describes an August 2020 deadline to submit a final protocol for said study without teaching or suggesting any details of such a protocol (e.g., weights, dose amounts, or dosing frequency). Moreover, 1254760rig1s000 is silent regarding any results, let alone a clinical response defined by complete Mayo score and a rectal bleeding subscore, as specified by the claims, as amended.
However, once a prima facie case of obviousness has been made the burden of going further is shifted to applicant. In re Keller, 642 F.2d 4B, 208 USPQ 871, 882 (CCPA 1981). This applicant has not done, but rather argues the references individually and not their combination. One cannot show non-obviousness by attacking references individually where the rejections are based on a combination of references. In re Young 403 F.2d 759, 150 USPQ 725 (CCPA 1968).
The '572 publication is Applicant's own work and describes "methods for treating patients with anti-α4β7 antibody comprising predicting outcome of the antibody therapy" (see Abstract). The `572 publication is cited for teaching a vedolizumab population pharmacokinetic model. Although the Office acknowledges that said model is based on an adult population (see page 50, Table 1, Age, years: 36 (18-78)), the Office alleges that one of ordinary skill could still use said model to reach a fixed 200 mg dose for a patient 2 to 10 years old, as specified by the claims. The `572 publication states that “[b]ody weight was chosen to represent changes in vedolizumab pharmacokinetics as a function of body size and was described using an allometric model with a reference weight of 70 kg. The other continuous covariates of albumin, fecal calprotectin, partial Mayo score, age, and CDAI score entered the model as power functions normalized by a reference value (typically near the observed median value of the data)” (see page 51, lines 19-24). Notably, the ‘572 publication states that “[e]xtreme values of albumin and weight had important effects on drug clearance” and that “clearance increased as... weight increased” (see page 60, lines 20-22). Given that the ‘572 publication teaches that “pharmacokinetics or pharmacodynamics factors can indicate whether a patient will respond to treatment with an anti-α4β7 antibody, such as vedolizumab” and that “clearance increased as... weight increased” (see page 2, lines 22-23 and page 60, lines 21-22), one of ordinary skill in the art would not be motivated based on the teachings of the ‘572 publication to adjust the 5-6 mg/kg dose described in Singh et al. as achieving remission in pediatric patients 7-17 years old for a small pediatric patient who is 2 to 10 years old and weighs 10 kg to 30 kg, as claimed, let alone have an expectation that 200 mg doses would be safe (e.g., from 50-60 mg to 200 mg for a patient who weighs 10 kg). Indeed, Applicant’s specification states that:
[i]t is surprising that administration of a fixed dose of 100 mg, 150 mg, or 200 mg, e.g., from a dosage form, e.g., a vial, manufactured to deliver about 95 to 110 mg, 100 mg, 108 mg, 145 mg to 155 mg, 150 mg, 155 mg to 170 mg, 190 to 210 mg or 200 mg of an anti-α4β7 antibody, e.g., vedolizumab, to a small pediatric patient, e.g., 5 kg to 35kg, 10 kg to 30 kg, or less than 30 kg, is safe. In these embodiments, the smallest patients may be administered at least 20 mg/kg anti-α4β7 antibody, a dose level unprecedented in therapeutic use of anti-α4β7 antibody, e.g., vedolizumab, wherein the smallest adults are administered about 5 to 7 mg/kg anti-α4β7 antibody from a 300 mg dosage form (see page 32, second para. of the specification as filed; emphasis added).
Applicant submits that the ‘885 publication and the ‘778 publication are Applicant’s own work and are each cited for teaching a 200 mg dose. As a first matter, Applicant reiterates that the `778 publication does not teach or suggest a 200 mg dose for ulcerative colitis, as claimed, and instead describes treating a gastrointestinal immune-related adverse event (gi-irAE) in a subject undergoing an immune oncology treatment. Moreover, the ‘885 publication and the ‘778 publication do not teach or suggest that a 200 mg dose would be safe and/or effective for treating ulcerative colitis in a smaller pediatric patient who is 2 to 10 years old and weighs 10 kg to less than 30 kg, let alone capable of achieving the defined clinical response and clinical remission at week 14 of treatment.
This is not found convincing because given that the vedolizumab treats ulcerative colitis of patients of 7-17 years old. The overlapping age range between Singh and the claimed invention is 7-10 years with a body wight of 23kg to 30 kg, respectively, which is outside the measured baseline body weights range measured by the `572 publication and that Singh shows that doses between 6 mg/kg (i.e, 138mg to 180 mg) is less effective in treating UC while 300 mg is effective for treating pediatric ulcerative colitis patient at any time point, those skilled in the art would be motivate to use a low dose than 300 mg of vedolizumab such as 200 mg taught by the `778 and 885 publications that would result in the treatment of a pediatric patient with moderately active ulcerative colitis taught by Singh with reasonable exaptation of success. In the words of KSR, “a finite number of identified, predictable solutions” may support a conclusion of obviousness.
"[I]t is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456 (CCPA 1955); see also In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003). "Only if the 'results of optimizing a variable' are 'unexpectedly good' can a patent be obtained for the claimed critical range." In re Geisler, 116 F.3d 1465, 1469 (Fed. Cir. 1997) (quoting In re Antonie, 559 F.2d 618, 620 (CCPA 1977)). "[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272, 276 (CCPA 1980). Applicant’s claims and arguments fail under these tests.
9. Claims 69, 79, 81, 82, 87-89, 100-103 and 108-111 stand rejected under 35 U.S.C. 103 as being unpatentable over Shen et al (American Journal of Gastroenterology: October 2015, 110, p S845) and/or EMA/719224/2014 (December 12, 2014), each in view of Singh et al (Inflamm Bowel Dis 2016;22:2121–2126) or Healio (May 2015) and US 20140341885 or WO2016105572 (IDS) or WO/2017/165778, as is evidenced by the specification on page 15, 2nd ¶).
Shen et al teach that age of IBD at diagnosis does not affect vedolizumab (aka. a recombinant humanized immunoglobulin G1 (IgG1) monoclonal antibody comprising the claimed SEQ ID NO: 4-9) response, but total years of disease may predict clinical remission in the ulcerative colitis population. Shen teaches that VDZ was shown to effectively treat UC in clinical trials as both primary therapy and as salvage therapy for those who were refractory to anti-TNF medications. Shen et al teach that 420 subjects prescribed biologics, 110 were prescribed VDZ and 70 started VDZ, receiving on average 6.4 doses. Only 4% (3/70) had never failed an anti-TNF, while 21.4% (15/70), 54.3% (38/70), and 20% (14/70) had failed one, two, and three anti-TNF, respectively. Average age of diagnosis was 27.5 (5-71(years old)) (i.e., encompass pediatric patients about 5-10 years old with an average body weight of 17.9kg (5 Yrs old body), 19.9 (6 Yrs), 22.4kg (7 Yrs), 25.8 (8 Yrs), 28.1 (9 yrs). UC cohorts stratified by duration of disease had a trend toward significance to achieve clinical remission if there was > 8.8 years of disease compared to those with < 8.8 years of disease; 66.7% (8/12) vs 28.6% (4/14), respectively (p=0.11). This was not seen with regard to clinical response in the UC cohort 35.7% (5/14) for those with < 8.8 years compared to 50% (6/12) for those with > 8.8 years of disease (p=0.69). UC and CD cohorts stratified by age at diagnosis (> 30 years vs < 30 years) showed no statistically significant difference in clinical response or remission. Changes in ESR or CRP and need for steroids or surgery once VDZ was started, did not reach statistical significance when stratified by age at diagnosis or duration of disease. Shen et al concluded that age of IBD diagnosis does not appear to impact response to vedolizumab, and should not be taken into consideration when prescribing the medication. Duration of disease may predict clinical remission for UC patients and further studies need to be performed.
European Medicines Agency provides Opinion of the Paediatric Committee on the acceptance of a modification of an agreed Paediatric Investigation Plan with intravenous use of vedolizumab in the treatment of moderately (PUCAI score of 35-64) to severely (PUCAI score of 65-85) active ulcerative colitis (sections 2.2.1 and 2.2.4) in children from 4 to less than 18 years of age (section 2.1.2). The EMA opinion further teaches studies to determine the pharmacokinetics, pharmacodynamics, safety, and tolerability of vedolizumab in pediatric patients with inflammatory bowel disease (sections 2.1.4 and 2.2.4). Moreover, randomized, double-blind, placebo-controlled two-dose, three-arm, multicenter study of the induction and maintenance of clinical response and remission by vedolizumab in pediatric patients with moderate to severe Crohn’s disease and ulcerative colitis (sections 2.1.4 and 2.2.4). EMA opinion states that the route of administration is intravenous (see page 1 under Route(s) of administration and page 2, article 1, sections 1.1, 1.2). Further, EMA teaches that children from birth to less than 4 years (see sections 1.1 and 1.2).
The reference teachings differ from the claimed invention only in the recitation of a dose regimen of 0, 2, 6, 8 weeks of 200 mg of vedolizumab in claims 69 and 79, a fourth dose at either 14 after the first dose and 8 weeks thereafter weeks in claims 69, 81, 82.
Singh et al teachings have been discussed, above.
Healio teaches that two studies presented during DDW 2015 showed safety and efficacy of Entyvio (aka, vedolizumb) used in pediatric patients with a range of inflammatory bowel diseases. Vedolizumab was associated with week 6 and week 14 remission in both pediatric ulcerative colitis and pediatric Crohn’s disease patients, with UC patients having higher rates of remission than Crohn’s. Importantly, Healio teaches that Singh presented results of a prospective observational study in which they initiated Entyvio (vedolizumab, Takeda; 6 mg/kg, maximum 300 mg) — off label — via intravenous infusion in pediatric patients. The study looked at 23 patients (15 with Crohn’s; eight with ulcerative colitis) enrolled between June 2014 and October 2014; median age of vedolizumab initiation was 14 years (average body weight 50 kg). Week 6 and week 14 remission rates overall were 56.5% and 57.1%, respectively, and week 6 remission predicted week 14 remission (P < .05). Additionally, Healio showed that there was an association between duration from anti-TNF therapy to vedolizumab treatment and remission.
However, `752 publication teaches a vedolizumab population pharmacokinetic model, NONMEM 7, was developed using the first-order conditional estimation with η-ε interaction (FOCEI) method and extensively sampled phase 1 and 2 data (see the entire document, page 47, lines 20+ and page 49, lines 12+). The objectives were to (1) characterize the pharmacokinetics of vedolizumab in patients who received repeated IV infusion of vedolizumab 300 mg for up to 52 weeks; (2) identify clinically relevant determinants of vedolizumab clearance in patients; and (3) describe the pharmacokinetic-pharmacodynamic relationship of vedolizumab in patients using MAdCAM-1 as the pharmcodynamic endpoint (see page 42, under Example 1). The `752 publication teaches that the study population consisted of 2554 individuals who contributed 18427 evaluable vedolizumab serum samples, including 87 healthy volunteers from the phase 1 study, 46 patients from the phase 2 study (UC), and 891, 1115, and 415 patients from the phase 3 GEMINI 1 (UC), GEMINI 2 (CD), and GEMINI 3 (CD) studies, respectively. Demographics and other characteristics of the pharmacokinetic analysis population are summarized in Table 1. The analysis population consisted of 1290 men and 1264 women with ages ranging from 18 to 78 years and baseline body weights ranging from 28 to 170 kg. A total of 1530 individuals had CD and 937 had UC; 87 were healthy volunteers ( see page 49, under Pharmacokinetic Analysis Population). The `752 publication teaches that vedolizumab is administered at a dose of 50 mg, 100 mg, 180 mg, 300 mg, or 600 mg (see page 29, line 20). The `752 publication teaches that the vedolizumab is administered at 0, 2 and 6 (induction) weeks and every four weeks or every eight weeks thereafter (maintenance) (i.e., 0, 2, 6, every 8 (i.e., 14 wks after 1st dose) weeks) (see page 29-30, bridging ¶, see published claims 34-35, 45-52). The `572 publication teaches and claims that methods of treating a human patient suffering from Inflammatory Bowel Disease (IBD) including ulcerative colitis with 300 mg vedolizumab, wherein the patient has an inadequate response with, lost response to or was intolerant to a TNF blocker (see claims 53-59). The `572 publication teaches that Vedolizumab is indicated for the treatment of patients with moderately (PUCAI score of 35-64) to severely (PUCAI score of 65-85) active ulcerative colitis (UC) (see page 14, lines 13+, page 42, lines 13+). Vedolizumab is an integrin receptor antagonist indicated for adult patients with moderately to severely active UC or CD who have had an inadequate response with, lost response to, or were intolerant to a tumor necrosis factor (TNF) blocker or immunomodulator, or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids (page 24, lines 19+). The `572 teaches that vedolizumab is and IgG1 antibody (see pages 1-2, bridging ¶; page 59, lines 9+, page 24, top ¶).
The `885 publication teaches that methods of treating human patient suffering from IBD with a humanized immunoglobulin having binding specificity for human α4β7 integrin, the humanized immunoglobulin, vedolizumab, is administered in a final dosage of 200 mg (see claims 24-26, 29-30, 34-35, 53, [0037], [0141], [0142]). The formulation of the invention can be for subcutaneous, intravenous [0022].
Given that the vedolizumab treats ulcerative colitis of patients of 5-9 years old having body weight of 18-28 kg which is outside the measured baseline body weights range measured by the `572 publication and that Healio shows that doses between 6 mg/kg up to maximum 300 mg are effective for treating pediatric ulcerative colitis patient, those skilled in the art would found it obvious to use the population model taught by the `572 publication to determine the fixed dosing with vedolizumab in the treatment of pediatric patients with moderately to severely active UC who have a body weight of less than 30 kg taught by European Medicines Agency and Shen et by determine the pharmacokinetic analysis population model taught by the `572 publication for the patients having less than 30 kg body weight which would result in a fixed dose of 200 mg dose as taught by the `885 publication.
The `778 publication teaches and claims methods of treating a gastrointestinal immune-related adverse event (gi-irAE) in a mammalian subject undergoing an immune oncology treatment, comprising administering a therapeutically effective amount of a polypeptide that inhibits MAdCAM- α4β7 integrin binding to the subject, wherein the polypeptide that inhibits MAdCAM- α4β7 integrin binding is an anti-α4β7 integrin antibody and is administered at a unit dose of about: 200 mg to a human subject (see claims). The `778 vedolizumab is administered at a dose of 50 mg, 100 mg, 108 mg, 165 mg, 200mg, 216mg, 300 mg, 450 mg, 500 mg, or more. 200, 300, or 450 mg vedolizumab may be administered by intravenous infusion at zero, two, and six weeks, and then at four weeks intervals or eight week intervals thereafter. In some embodiments, 200, 300, or 450 mg vedolizumab may be administered by intravenous infusion at zero, two, and six weeks, and then at two, three or four week intervals [0065]. The `778 publication teaches that the polypeptide that inhibits MAdCAM- α4β7 integrin binding is administered at least four times, where the second dose is administered about two weeks after the first administration, the third dose is administered about four weeks after the first administration, and the fourth dose is administered about 12 weeks after the first administration [0010]. The `778 publication teaches subjects treated by the methods provided by the invention exhibit reduced, or in some embodiments, no grade 3 or 4 (no: Grade 3 colitis, Grade 4 (or Grade 3 that persists or worsens over 3-5 days) colitis or diarrhea), only grade 1-2 diarrhea, or if any grade 2 occurs, that the symptoms resolve, e.g., by symptomatic antidiarrheal treatment without adding prednisone or anti-TNF-α treatment [0069]. It is noted that moderate PUCAI score of 35-64)/ severely (PUCAI score of 65-85) colitis (Grade 2 and above). The `778 publication teaches that the treatment exhibits reducing or eliminating the use of: corticosteroids ( oral or systemic), antibiotics ( oral or parenteral), non-corticosteroid immunosuppressive medication (e.g. anti-TNF-α agents), lower endoscopy, hospitalizations, or a combination thereof [0017].
Given that the vedolizumab treats ulcerative colitis of patients of 5-9 years old have body weight of 18-28 kg which is outside the measured baseline body weights range measured by the `572 publication and that Healio shows that doses between 6 mg/kg up to maximum 300 mg are effective for treating pediatric ulcerative colitis patient, those skilled in the art would be motivate to use a low dose of vedolizumab such as 200 mg taught by the `778 publication in the treatment of a pediatric patient with moderately to severely active ulcerative colitis taught by European Medicines Agency and Shen et.
A person having ordinary skill in the art would have found it obvious to determine the optimum pediatric patient doses of VDZ that enhances anti-UC effect of result-effective variables known in the art. Recognition that a property (VDZ treatment results in UC remission) is affected by the variable (age/weight of the patient) is sufficient to find the variable result-effective. The Board stated that "all that remained to be achieved over the prior art was the determination that a specific dose within a previously suggested dose range, and its corresponding dosing schedule, would have been safe and effective for the treatment of human patients." Genzyme Therapeutic Prods. v. Biomarin Pharms., No. 2015-1720.
"[I]t is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456 (CCPA 1955); see also In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003). "Only if the 'results of optimizing a variable' are 'unexpectedly good' can a patent be obtained for the claimed critical range." In re Geisler, 116 F.3d 1465, 1469 (Fed. Cir. 1997) (quoting In re Antonie, 559 F.2d 618, 620 (CCPA 1977)). "[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272, 276 (CCPA 1980).
The functions recited in the wherein clause flow naturally from the teachings of the prior art. Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985 (“The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.”), and Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347 (Fed. Cir. 1999) (“[T]he discovery of... a scientific explanation for the prior art's functioning, does not render the old composition patentably new to the discoverer.”)). Here, the recited functional outcome would naturally and necessarily flow from inhibition of α4ß7 by administering Vedolizumab. Accordingly, the prior art teaches the same method, the product used in the reference method are the same as the claimed method. Therefore, the claimed functional outcome would naturally and necessarily flow from inhibition of α4ß7 with the Vedolizumab in treating pediatric colitis in a human subject. Moreover, Shen et al teach that UC cohorts stratified by age at diagnosis (> 30 years vs < 30 years) showed no statistically significant difference in clinical response or remission.
The specification on page 15, 2nd discloses that PUCAI score 35 to 64 moderate disease and 65 to 85 severe disease.
With respect to recited results achieved “wherein the pediatric patient achieves a clinical response defined as a reduction in complete Mayo score of ≥3 points and ≥30% from a baseline and a decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤ 1 point, and achieves clinical remission with a Pediatric UC Activity Index (PUCAI) score of less than 10 at 14 weeks after the initial dose” flow naturally from the teachings of the prior art. The functions recited in the wherein clause flow naturally from the teachings of the prior art. Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985 (“The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.”), and Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347 (Fed. Cir. 1999) (“[T]he discovery of... a scientific explanation for the prior art's functioning, does not render the old composition patentably new to the discoverer.”)). Here, the recited functional outcome would naturally and necessarily flow from inhibition of α4ß7 by administering Vedolizumab. Accordingly, the