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 .
Status of the Claims
Claims 1-2, 4-8, 10, 12, 15-20, 24, and 27-30 are pending (claim set as filed on 01/06/2026).
Applicant’s election of species in the reply filed on 07/14/2025 is acknowledged. Applicant elects the following species for search purposes:
a patient who is less than 5-years old and suffers from Hirshsprung disease;
a GDNF polypeptide by amino acids 78-211 of SEQ ID NO: 1 and a saline solution;
injection into the distal colon;
prior to surgical removal of the aganglionic or hypoganglionic segment; and
restores distal colon motility.
Thus, claims 17-18 are withdrawn as being directed to the non-elected species.
Therefore, claims 1-2, 4-8, 10, 12, 15-16 (rejoined), 19-20 (rejoined), 24, and 27-30 are under examination.
Priority
This application is a 371 of PCT/CA2020/051746 filed on 12/18/2020, which has a
PRO 62/950,781 filed on 12/19/2019.
Terminal Disclaimer
The terminal disclaimer filed on 01/06/2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of application no. 18/567,915 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Withdrawal of Rejections
The response and amendments filed on 01/06/2026 are acknowledged. Any previously applied minor objections and/or minor rejections (i.e., formal matters), not explicitly restated herein for brevity, have been withdrawn necessitated by Applicant’s formality corrections and/or amendments. For the purposes of clarity of the record, the reasons for the Examiner’s withdrawal, and/or maintaining if applicable, of the substantive or essential claim rejections are detailed directly below and/or in the Examiner’s response to arguments section.
Briefly, the previously applied obviousness rejection over Corfas in view of Studer has been withdrawn necessitated by Applicant’s amendment to delete the claimed phrase of “enteric neuropathy” which thereby severs the nexus between the two references. However, note below that a new ground of rejection is set forth with a new primary reference by Bondurand while previously cited Corfas and Studer are reprised as secondary references because they remain applicable to addressing the claim limitations of distal colon and recombinant GDNF.
Briefly, the previously applied non-statutory double patenting rejection over application no. 18/567,915 has been withdrawn necessitated by Applicant’s filing of a terminal disclaimer as indicated above.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
New Grounds of Rejection Necessitated by Amendment
Claim Rejections - 35 USC §103, Obviousness
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-2, 4-8, 10, 12, 15-16, 19-20, 24, and 27-30 are rejected under 35 U.S.C. 103 as being unpatentable over Bondurand (Mouse models of Hirschsprung disease and other developmental disorders of the enteric nervous system: old and new players, 2016 - cited by the ISA and in the IDS filed on 10/11/2023) in view of Studer (US 2018/0291339 A1 - previously cited) and Corfas (US 2016/0045487 A1 - previously cited).
Regarding claims 1’s limitation, 15-16, and 19-20 pertaining to the patient/subject population, Bondurand’s general disclosure relates to studies involving the pathologies of Hirschsprung disease (HSCR, intestinal aganglionosis) (see abstract & page 139: Introduction). Bondurand further discloses “the first mouse model of HSCR was generated by targeting the Ret gene. This tyrosine kinase receptor interacts with four distinct ligands [glial cell line-derived neurotrophic factor (Gdnf), neurturin (Nrtn), artemin (Artn) and persephin (Pspn)]. Each of these activates Ret by binding to the glycosylphosphatidylinositol-linked Gdnf family of co-receptors (Gfra1 to 4). In mice, total Ret deficiency causes complete intestinal aganglionosis. Ret-/- mice additionally present with kidney agenesis and die at birth. Gdnf and Gfra1 deletions cause nearly identical phenotypes, indicating that they are the critical Ret activators during fetal development” and “In total, data from these models show that Ret signaling is essential for ENS precursor proliferation, migration, differentiation, survival, and neurite growth. Gdnf/Ret signaling can also influence formation of specific subtypes of neurons” (see page 140, right col. 2nd ¶, & page 143, right col., and Table 1).
However, Bondurand does not teach: administrating a recombinant GDNF polypeptide into the distal colon of the subject (claim 1’s last limitation, claims 8 and 29-30); or a patient who is less than 5-years old (claims 27-28).
Studer teaches the treatment of Hirschsprung’s disease (see ¶ [0032]-[0034]). Studer discloses “Defects in ENS development are responsible for a range of human disorders including Hirschsprung’s disease (HD). HD is a debilitating genetic disorder caused by the developmental failure of ENS progenitors to migrate into the GI tract in particular the distal colon” (see ¶ [0004]). Studer teaches “molecule that enhances maturation of enteric nervous system precursors into enteric neurons … selected from the group consisting of growth factors” including glial cell line derived neurotrophic factor (GDNF) (see ¶ [0030]).
Regarding the administration site, Studer teaches administration may be systemically or locally infused into the gastrointestinal tract (e.g., the colon) of a subject (see ¶ [0050]-[0051]) or “can be administered (injected) directly to a subject’s intestine region, e.g., small intestine, colon, cecum, and/or rectum … of a subject suffering from an ENS disorder (e.g., HD) (see ¶ [0390]).
Regarding a recombinant GDNF polypeptide, Corfas teaches compositions comprising combinations of XIB4035 and a GFRα ligand (e.g., GDNF). Corfas further teaches “GDNF is administered, and optionally, is administered locally”, “the GDNF polypeptide is administered by injection”, and “the exogenous administration of GDNF provides high levels of GDNF throughout the body” (see ¶ [0017]-[0018], [0079]). Corfas teaches administration of a recombinant therapeutic such as a recombinant a GFRα ligand (e.g., GDNF) either directly to the site of a potential or actual disease affected tissue to an organ where the polypeptide will have a therapeutic effect (see ¶ [0119], [0126]).
Regarding claims 2 and 4-5, Corfas teaches by “GDNF polypeptide” is meant a polypeptide having 85% or greater sequence identity to NCBI Reference No. P39905 or a fragment thereof (see ¶ [0033]-[0034]).
Regarding claim 7 pertaining to the pharmaceutically acceptable carrier, Corfas discloses that “the compositions or agents disclosed herein may be administered systemically, for example, formulated in a pharmaceutically-acceptable buffer such as physiological saline” (see ¶ [0103]-[0104]).
Regarding claims 6 and 10 pertaining to the dosages, Corfas discloses “By ‘effective amount’ is meant the amount of a required to ameliorate the symptoms of a disease relative to an untreated patient. The effective amount of active compound(s) used to practice the present invention for therapeutic treatment of a disease varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amount is referred to as an “effective” amount” (see ¶ [0043], [0081]). Corfas teaches treatment of once a day or twice a day (see ¶ [0144]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer a pharmaceutical composition comprising a recombinant GDNF in saline into the distal colon of subject suffering from Hirschsprung disease (HDSCR) following the guidance of the cited references. The ordinary artisan would have been motivated to do so is because:
Bondurand critically teaches “Ret signaling is essential for ENS precursor proliferation, migration, differentiation, survival, and neurite growth. Gdnf/Ret signaling can also influence formation of specific subtypes of neurons” (see page 140, right col. 2nd ¶);
Studer discloses that Hirschsprung disease “is a debilitating genetic disorder caused by the developmental failure of ENS progenitors to migrate into the GI tract in particular the distal colon” (see ¶ [0004]);
Corfas suggests recombinant GDNF for in vivo administration, where “GDNF is administered, and optionally, is administered locally”, “the GDNF polypeptide is administered by injection”, and “the exogenous administration of GDNF provides high levels of GDNF throughout the body” (see ¶ [0017]-[0018], [0079]).
Therefore, it would have been reasonably apparent to one of ordinary skill in the art to administer a recombinant GDNF polypeptide into the distal colon of a subject in order to promote or permit the induction of permanent formation of new functioning enteric neurons for the treatment of intestinal hypoganglionic or Hirschsprung disease because, in particular, the primary reference of Bondurand suggests that Ret signaling via GDNF is critical or essential for ENS precursor proliferation, migration, differentiation, survival, and neurite growth. Moreover, Studer discloses that the distal colon is particularly affected in HD and Corfas discloses a pharmaceutical composition of recombinant GDNF for in vivo application. Accordingly, the claimed invention is prima facie obvious to an ordinary artisan the following the guidance of references.
Regarding claim 12, Studer discloses “Children suffering from HD are currently treated by surgical removal of the aganglionic portion of the gut. While life-saving, the surgery does not address permanent dysfunction of the remaining GI tract in surviving patients” (see Studer at ¶ [0388]). The MPEP 2144.04 states that “(selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results)”. Thus, whether the claimed method is performed prior to and/or after surgery, the claimed sequence would have been within the purview of the ordinary artisan to determine.
Regarding claim 24, Studer teaches “An optimal effect include, but are not limited to, repopulation of gut, repopulation of colon, and repopulation of gut and colon of a subject suffering from an ENS disorder (e.g., HD), and/or improved function of the subject’s intestine” (see ¶ [0396]).
Regarding claims 27-28 pertaining to the age of the subject, although the cited references do not explicitly teach a human subject that is less than 5 years old, however such parameter would nonetheless be prima facie obvious to an ordinary artisan because Corfas discloses “to practice the present invention for therapeutic treatment of a disease varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen” (see Corfas at ¶ [0043]) and Studer similarly discloses “several factors are typically taken into account when determining an appropriate dosage to achieve an effective amount. These factors include age, sex and weight of the subject” (see Studer at ¶ [0397]). Studer also teaches animal studies in 3-6 weeks rodent models (see Studer at ¶ [0446]) and suggest “children suffering from HD” (see Studer at ¶ [0388]). Thus, a human subject that is less than 5 years old would have been readily apparent to an ordinary artisan following the guidance of the cited references.
Conclusion
No claims were allowed.
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.
Correspondence Information
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/NGHI V NGUYEN/Primary Examiner, Art Unit 1653