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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) were submitted on 2/12/2024, 12/12/2024, and 7/15/2025 before the mailing of a first office action. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). Specifically, sequences located at page 1, line 9; page 10, line 29; page 11, line 7; page 11, line 10; page 11, line 15; page 20, line 2; page 20, line 8; page 20, line 14; page 20, line 20; and page 20, line 27 lack sequence identifiers.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because of the following informalities: Sequences located at page 1, line 9; page 10, line 29; page 11, line 7; page 11, line 10; page 11, line 15; page 20, line 2; page 20, line 8; page 20, line 14; page 20, line 20; and page 20, line 27 lack sequence identifiers. Appropriate correction is required.
Claim Status
Claims 1, 6-13, 16-18, and 20-27, filed 2/12/2024, are pending. Claims 1, 6-13, 16-18, and 20-27 are under examination. Claims 3-5, 14-15, and 19 are canceled.
Claim Interpretation
For clarity of the record, ZP1848 is interpreted to refer to glepaglutide with a sequence of H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2.
Claim 1 is interpreted to include the case wherein the subject is not currently being treated at all. Therefore, initial administration of ZP1848 is included in the scope of claim 1. Furthermore, such an initial administration of ZP1848 would not require a dose adjustment.
Claim Objections
Claims 1, 6-13, 16-18, and 20-27 are objected to because of the following informalities. MPEP 2173.05(s) states: “Where possible, claims are to be complete in themselves.” Claims 1, 6-13, 16-18, and 20-27 directly or through dependency reference ZP1848. For ease of reading and reference, Applicant should reference the name “glepaglutide” and the sequence of glepaglutide in the claims at least once. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 6-13, 16-18, and 20-22, and 25 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1, claim 1 recites: “A method of prophylaxis or treatment of a condition responsive to ZP1848 in a subject, comprising administering ZP1848 or a pharmaceutically acceptable salt thereof to said subject, wherein said subject has at least moderate renal impairment or is one for whom an adjusted dose of teduglutide would be indicated as a result of renal impairment, wherein no dose adjustment of ZP1848 or said salt is required.”
The phrase “wherein no dose adjustment of ZP1848 or said salt is required” is only meaningful in the case where the subject is already receiving some known dose of ZP1848. In the case where the subject is not being treated at all or is being treated with a different compound and ZP1848 is just being started, this dose adjustment clause has no frame of reference. Because it is not clear whether the subject referenced in claim 1 is already receiving ZP1848 or not, claim 1 is indefinite.
Regarding claims 6-11, claim 1 is rejected as described above. These claims depend upon claim 1 and do not resolve the indefiniteness. Consequently, claims 6-11 are rejected.
Regarding claim 12, claim 12 uses the same phrase “wherein no dose adjustment of ZP1848 or said salt is required”. For the same reasons as claim 1, it is not clear whether the subject referenced in claim 12 is already receiving ZP1848 or not and claim 12 is indefinite.
Regarding claims 13, 17, 18, and 20, claim 12 is rejected as described above. These claims depend upon claim 12 and do not resolve the indefiniteness. Consequently, claims 13, 17, 18, and 20 are rejected.
Regarding claim 16, claim 16 uses the same phrase “wherein no dose adjustment of ZP1848 or said salt is required”. For the same reasons as claim 1, it is not clear whether the subject referenced in claim 16 is already receiving ZP1848 or not and claim 16 is indefinite.
Regarding claim 20, claim 20 recites the limitation "said dosing regime" in line 2. There is insufficient antecedent basis for this limitation in the claim. Neither claim 18 nor claim 12 recites “dosing regime”. Claim 20 is rejected.
Regarding claim 21, claim 21 recites the limitation "unadjusted dose" in line 2. There is insufficient antecedent basis for this limitation in the claim in claim 1. Claim 1 does not recite an element “unadjusted dose”. Also, claim 21 is dependent upon claim 1 and does not resolve the indefiniteness created by claim 1 above.
Claim 21 also uses the phrase "e.g.", which renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
For these reasons, claim 21 is rejected.
Regarding claim 22, claim 21 is rejected as described above. Claim 22 also recites “unadjusted dose” in line 2. There is insufficient antecedent basis for this limitation in the claim in claim 1, upon which this claim is dependent. Also, claim 21 is dependent upon claim 22 as does not resolve the indefiniteness created by claim 21 above. For these reasons, claim 22 is rejected.
Regarding claim 25, the phrase "e. g." renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 23, 25, and 26 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Suzuki et al. (Suzuki, al. Journal of medicinal chemistry 63.3: 905-927 (2019)).
Regarding claim 23, claim 23 recites a pharmaceutical kit comprising ZP1848 or a pharmaceutically acceptable salt thereof and information that no dose adjustment of ZP1848 is required for subjects having at least moderate renal impairment.
Suzuki discloses the usage of ZP1848:
“Glepaglutide (ZP1848), first published in a patent application in 2006, (97) is a highly potent GLP-2 selective 39 amino acid peptide discovered by Zealand Pharma. (97) Zealand is looking to develop glepaglutide as a potential best in class GLP-2 treatment for patients with SBS.
Glepaglutide has the sequence [Gly2, Glu3, Thr5, Ser8, Leu10, Ala11,16,24,28] hGLP-2(1–33)-(Lys)6-NH2 (Figure 3) and incorporates a number of design strategies (Figure 4). These include (i) addition of six lysine residues to the C-terminus to modify the charge state which may aid solubility and physicochemical properties, (ii) replacement of four residues by alanine in a region that connects the seven-transmembrane-binding residues and the extracellular domain-binding regions, and (iii) optimization of the N-terminal region with five changes to the sequence presumably to optimize pharmacokinetic and potency properties.
In preclinical studies, glepaglutide (ZP1848) was shown to demonstrate greater intestinotrophic activity in the small intestine compared to the reference agent teduglutide. (97) In a model of small intestinal inflammation induced by indomethacin, glepaglutide was effective in reducing ulceration as well as inflammatory markers in tissue within the small intestine, (97,98) further supporting an anti-inflammatory and mucosal regenerative role for GLP-2.” (Suzuki et al., page 912, col. 1, para. 4)
MPEP 2112.01(III) states: “Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004)”.
Consequently, claim 23 is anticipated by Suzuki et al. and rejected.
Regarding claim 25, claim 23 is anticipated as described above. Claim 25 further recites the case wherein each said dose is between 1 mg and 20 mg, e.g. between 5 mg and 15 mg, between 7 mg and 12 mg, or between 9 mg and 11 mg.
Suzuki discloses: “At all doses tested (0.1, 1, 10 mg) the drug was reported to be safe and well tolerated.” (Suzuki et al., page 912, col. 2, para. 1).
The 10 mg dosage disclosed by Suzuki anticipates the recited ranges of claim 25. Consequently, claim 25 is anticipated by Suzuki and rejected.
Regarding claim 26, claim 23 is anticipated as described above. Claim 26 further recites the case wherein each individual dose is about 10 mg.
Suzuki discloses: “At all doses tested (0.1, 1, 10 mg) the drug was reported to be safe and well tolerated.” (Suzuki et al., page 912, col. 2, para. 1).
The 10 mg dosage disclosed by Suzuki anticipates the dosage recited by claim 26. Consequently, claim 26 is anticipated by Suzuki and rejected.
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 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 1, 2, 6-13, 16-18, 20-22, and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Suzuki et al. (Suzuki, et al. Journal of medicinal chemistry 63.3: 905-927 (2019)) in view of Banerjee et al. (Banerjee, et al. QJM 95.1: 37-40 (2002)).
Regarding claim 1, claim 1 recites a method of prophylaxis or treatment of a condition responsive to ZP1848 in a subject, comprising administering ZP1848 or a pharmaceutically acceptable salt thereof to said subject, wherein said subject has at least moderate renal impairment or is one for whom an adjusted dose of teduglutide would be indicated as a result of renal impairment, wherein no dose adjustment of ZP1848 or said salt is required.
Suzuki discloses the usage of ZP1848 for treating short bowel syndrome:
“Glepaglutide (ZP1848), first published in a patent application in 2006, (97) is a highly potent GLP-2 selective 39 amino acid peptide discovered by Zealand Pharma. (97) Zealand is looking to develop glepaglutide as a potential best in class GLP-2 treatment for patients with SBS.
Glepaglutide has the sequence [Gly2, Glu3, Thr5, Ser8, Leu10, Ala11,16,24,28] hGLP-2(1–33)-(Lys)6-NH2 (Figure 3) and incorporates a number of design strategies (Figure 4). These include (i) addition of six lysine residues to the C-terminus to modify the charge state which may aid solubility and physicochemical properties, (ii) replacement of four residues by alanine in a region that connects the seven-transmembrane-binding residues and the extracellular domain-binding regions, and (iii) optimization of the N-terminal region with five changes to the sequence presumably to optimize pharmacokinetic and potency properties.
In preclinical studies, glepaglutide (ZP1848) was shown to demonstrate greater intestinotrophic activity in the small intestine compared to the reference agent teduglutide. (97) In a model of small intestinal inflammation induced by indomethacin, glepaglutide was effective in reducing ulceration as well as inflammatory markers in tissue within the small intestine, (97,98) further supporting an anti-inflammatory and mucosal regenerative role for GLP-2.” (Suzuki et al., page 912, col. 1, para. 4)
Suzuki does not disclose the case wherein the subject has at least moderate renal impairment or is one for whom an adjusted dose of teduglutide would be indicated as a result of renal impairment.
However, Banerjee et al. discloses that renal failure is commonly associated with short bowel syndrome: “Short bowel syndrome (SBS), defined as intestinal failure with a small bowel remnant length of less than ∼150 cm,1 describes a malabsorptive state caused by extensive loss of small intestinal length. The usual causes are listed in Table 1. With advances in medical and intensive care, the numbers of patients surviving these procedures are likely to increase. The chronic nephrological consequences of the short bowel syndrome, in patients with jejuno‐ileal bypass procedures, have been recently comprehensively reviewed in this journal.2
We now complete the spectrum of nephropathies by reporting the case histories of a series of patients presenting to our service with acute renal failure caused by the SBS, describing the range of metabolic disturbances associated with the condition, and making recommendations for treatment.” (Banerjee et al., page 2, para. 1).
Regarding the no dose adjustment element, the claim scope of claim 1 has been interpreted to include the first dose. No dose adjustment is possible on the first dose, since there is nothing to compare it to. Consequently, this element is present.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use ZP1848 as disclosed by Suzuki on a subject with renal failure caused by SBS as disclosed by Banerjee.
A person of ordinary skill in the art would be motivated to do use ZP1848 in this manner to reduce ulceration and inflammatory markers in the small intestine to help improve small intestine absorption. This improvement in absorption could help alleviate the issues associated with short bowel syndrome: “The major problems following established SBS are related to fluid/electrolyte imbalance, deficiencies in calcium, magnesium, zinc and vitamins A, D, E, K and B12, hypergastrinaemia, bile salt depletion, protein‐calorie malnutrition, pancreatic maldigestion and oxalate nephrolithiasis. Acute renal failure in our patients was predominantly due to salt and fluid depletion, and sepsis, particularly central catheter‐related sepsis in those receiving parenteral nutrition.” (Banerjee et al., page 6, para. 5).
A person of ordinary skill in the art would have a reasonable expectation of success because Suzuki discloses that glepaglutide showed greater intestinotrophic activity compared to teduglutide. (Suzuki et al., page 912, col. 1, para. 6). Therefore, glepaglutide can boost intestinal activity and help alleviate the problems described by Banerjee.
Consequently, claim 1 is obvious over Suzuki et al. in view of Banerjee et al. and rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites the case wherein the subject has previously been treated with teduglutide at an adjusted dose.
Suzuki et al. discloses that: “In preclinical studies, glepaglutide (ZP1848) was shown to demonstrate greater intestinotrophic activity in the small intestine compared to the reference agent teduglutide. (97) In a model of small intestinal inflammation induced by indomethacin, glepaglutide was effective in reducing ulceration as well as inflammatory markers in tissue within the small intestine, (97,98) further supporting an anti-inflammatory and mucosal regenerative role for GLP-2.” (Suzuki et al., page 912, col. 1, para. 6).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to follow teduglutide treatment with glepaglutide treatment to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to use glepaglutide because Suzuki discloses that it has superior intestinotrophic activity compared to teduglutide and would have a reasonable expectation of success for the same reason.
Consequently, claim 2 is obvious over Suzuki et al. in view of Banerjee et al. and rejected.
Regarding claim 6, claim 1 is obvious as described above. Claim 6 further recites the case wherein the subject has moderate renal impairment, severe renal impairment, or end stage renal disease (ESRD).
Banerjee et al. discloses that renal failure is commonly associated with short bowel syndrome: “Short bowel syndrome (SBS), defined as intestinal failure with a small bowel remnant length of less than ∼150 cm,1 describes a malabsorptive state caused by extensive loss of small intestinal length. The usual causes are listed in Table 1. With advances in medical and intensive care, the numbers of patients surviving these procedures are likely to increase. The chronic nephrological consequences of the short bowel syndrome, in patients with jejuno‐ileal bypass procedures, have been recently comprehensively reviewed in this journal.2
We now complete the spectrum of nephropathies by reporting the case histories of a series of patients presenting to our service with acute renal failure caused by the SBS, describing the range of metabolic disturbances associated with the condition, and making recommendations for treatment.” (Banerjee et al., page 2, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use ZP1848 as disclosed by Suzuki on a subject with renal failure caused by SBS as disclosed by Banerjee.
A person of ordinary skill in the art would be motivated to do use ZP1848 in this manner to reduce ulceration and inflammatory markers in the small intestine to help improve small intestine absorption. This improvement in absorption could help alleviate the issues associated with short bowel syndrome: “The major problems following established SBS are related to fluid/electrolyte imbalance, deficiencies in calcium, magnesium, zinc and vitamins A, D, E, K and B12, hypergastrinaemia, bile salt depletion, protein‐calorie malnutrition, pancreatic maldigestion and oxalate nephrolithiasis. Acute renal failure in our patients was predominantly due to salt and fluid depletion, and sepsis, particularly central catheter‐related sepsis in those receiving parenteral nutrition.” (Banerjee et al., page 6, para. 5).
A person of ordinary skill in the art would have a reasonable expectation of success because Suzuki discloses that glepaglutide showed greater intestinotrophic activity compared to teduglutide. (Suzuki et al., page 912, col. 1, para. 6). Therefore, glepaglutide can boost intestinal activity and help alleviate the problems described by Banerjee.
Consequently, claim 6 is obvious over Suzuki et al. in view of Banerjee et al. and rejected.
Regarding claim 7, claim 1 is obvious as described above. Claim 7 further recites the case wherein the condition to be treated is a stomach or bowel disorder.
Suzuki discloses the usage of ZP1848 for treating short bowel syndrome:
“Glepaglutide (ZP1848), first published in a patent application in 2006, (97) is a highly potent GLP-2 selective 39 amino acid peptide discovered by Zealand Pharma. (97) Zealand is looking to develop glepaglutide as a potential best in class GLP-2 treatment for patients with SBS.” (Suzuki et al., page 912, col. 1, para. 4).
Consequently, claim 7 is obvious over Suzuki et al. in view of Banerjee et al. and rejected.
Regarding claim 8, claim 7 is obvious as described above. Claim 8 further recites the case wherein said stomach or bowel related disorder is ulcers, a digestion disorder, a malabsorption syndrome, short-gut syndrome, inflammatory bowel disease, celiac sprue (for example arising from gluten induced enteropathy or celiac disease), tropical sprue, hypogammaglobulinemic sprue, enteritis, regional enteritis (Crohn's disease), ulcerative colitis, small intestine damage or short bowel syndrome (SBS).
Suzuki discloses the usage of ZP1848 for treating short bowel syndrome:
“Glepaglutide (ZP1848), first published in a patent application in 2006, (97) is a highly potent GLP-2 selective 39 amino acid peptide discovered by Zealand Pharma. (97) Zealand is looking to develop glepaglutide as a potential best in class GLP-2 treatment for patients with SBS.” (Suzuki et al., page 912, col. 1, para. 4).
Consequently, claim 8 is obvious over Suzuki et al. in view of Banerjee et al. and rejected.
Regarding claim 9, claim 8 is obvious as described above. Claim 9 further recites the case wherein the condition is short bowel syndrome (SBS) in a subject receiving parenteral support (PS).
Banerjee discloses that if enough small intestine is lost, parenteral support may be required: “Some 40–50% of small intestine can usually be lost without major metabolic or nutritional sequelae, however if more than 75% is lost, maintenance of nutritional status, at least initially, usually requires parenteral nutrition. Adaptive mechanisms, including intestinal dilatation and increases in crypt depth and villus height can lead to progressive recovery of the remaining bowel. The pattern of presentation of the SBS also depends on the site of intestinal resection (jejunal or ileal resection), the loss or preservation of the ileocaecal valve and large bowel and co‐existent small intestinal, liver or pancreatic disease.” (Banerjee et al., page 39, col. 1, para.72).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use ZP1848 as disclosed by Suzuki on a subject with renal failure caused by SBS as disclosed by Banerjee that additionally needs parenteral support.
A person of ordinary skill in the art would be motivated to do use ZP1848 in this manner to reduce ulceration and inflammatory markers in the small intestine to help improve small intestine absorption. This improvement in absorption could help alleviate the issues associated with short bowel syndrome: “The major problems following established SBS are related to fluid/electrolyte imbalance, deficiencies in calcium, magnesium, zinc and vitamins A, D, E, K and B12, hypergastrinaemia, bile salt depletion, protein‐calorie malnutrition, pancreatic maldigestion and oxalate nephrolithiasis. Acute renal failure in our patients was predominantly due to salt and fluid depletion, and sepsis, particularly central catheter‐related sepsis in those receiving parenteral nutrition.” (Banerjee et al., page 6, para. 5).
A person of ordinary skill in the art would have a reasonable expectation of success because Suzuki discloses that glepaglutide showed greater intestinotrophic activity compared to teduglutide. (Suzuki et al., page 912, col. 1, para. 6). Therefore, glepaglutide can boost intestinal activity and help alleviate the problems described by Banerjee and reduce the need for parenteral support.
Consequently, claim 9 is obvious over Suzuki et al. in view of Banerjee et al. and rejected.
Regarding claim 10, claim 7 is obvious as described above. Claim 10 further recites the case wherein the condition is radiation enteritis, infectious or post-infectious enteritis, or small intestinal damage due to toxic or other chemotherapeutic agents.
Banerjee discloses that radiation enteritis is a common cause of short bowel syndrome in adults and children (Banerjee et al., page 2, Table 1).
Consequently, claim 10 is obvious over Suzuki et al. in view of Banerjee et al. and rejected.
Regarding claim 11, claim 7 is obvious as described above. Claim 11 further recites the case wherein the condition is a side effect of chemotherapy or radiation treatment in a human subject.
Banerjee discloses that radiation enteritis is a common cause of short bowel syndrome in adults and children (Banerjee et al., page 2, Table 1).
Consequently, claim 11 is obvious over Suzuki et al. in view of Banerjee et al. and rejected.
Regarding claim 12, claim 12 recites A method of increasing intestinal mass and/or promoting or increasing longitudinal intestinal growth in a subject, comprising administering ZP1848 or a pharmaceutically acceptable salt thereof to said subject, wherein the subject has at least moderate renal impairment or is one for whom an adjusted dose of teduglutide would be indicated as a result of renal impairment, wherein no dose adjustment of ZP1848 or said salt is required.
Suzuki discloses the usage of ZP1848 for increasing intestinal regeneration and therefore mass:
“In preclinical studies, glepaglutide (ZP1848) was shown to demonstrate greater intestinotrophic activity in the small intestine compared to the reference agent teduglutide. (97) In a model of small intestinal inflammation induced by indomethacin, glepaglutide was effective in reducing ulceration as well as inflammatory markers in tissue within the small intestine, (97,98) further supporting an anti-inflammatory and mucosal regenerative role for GLP-2.” (Suzuki et al., page 912, col. 1, para. 6)
Suzuki does not disclose the case wherein the subject has at least moderate renal impairment or is one for whom an adjusted dose of teduglutide would be indicated as a result of renal impairment.
However, Banerjee et al. discloses that renal failure is commonly associated with short bowel syndrome: “Short bowel syndrome (SBS), defined as intestinal failure with a small bowel remnant length of less than ∼150 cm,1 describes a malabsorptive state caused by extensive loss of small intestinal length. The usual causes are listed in Table 1. With advances in medical and intensive care, the numbers of patients surviving these procedures are likely to increase. The chronic nephrological consequences of the short bowel syndrome, in patients with jejuno‐ileal bypass procedures, have been recently comprehensively reviewed in this journal.2
We now complete the spectrum of nephropathies by reporting the case histories of a series of patients presenting to our service with acute renal failure caused by the SBS, describing the range of metabolic disturbances associated with the condition, and making recommendations for treatment.” (Banerjee et al., page 2, para. 1).
Regarding the no dose adjustment element, the claim scope of claim 1 has been interpreted to include the first dose. No dose adjustment is possible on the first dose, since there is nothing to compare it to. Consequently, this element is present.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use ZP1848 as disclosed by Suzuki to increase intestinal mass a subject with renal failure as disclosed by Banerjee.
A person of ordinary skill in the art would be motivated to do use ZP1848 in this manner to increase the mass of the small intestine to help improve small intestine absorption. This improvement in absorption could help alleviate the issues associated with short bowel syndrome: “The major problems following established SBS are related to fluid/electrolyte imbalance, deficiencies in calcium, magnesium, zinc and vitamins A, D, E, K and B12, hypergastrinaemia, bile salt depletion, protein‐calorie malnutrition, pancreatic maldigestion and oxalate nephrolithiasis. Acute renal failure in our patients was predominantly due to salt and fluid depletion, and sepsis, particularly central catheter‐related sepsis in those receiving parenteral nutrition.” (Banerjee et al., page 6, para. 5).
A person of ordinary skill in the art would have a reasonable expectation of success because Suzuki discloses that glepaglutide showed greater intestinotrophic activity compared to teduglutide. (Suzuki et al., page 912, col. 1, para. 6). Therefore, glepaglutide can increase the mass of the small intestine thereby boosting intestinal activity and helping to alleviate the problems described by Banerjee.
Consequently, claim 12 is obvious over Suzuki et al. in view of Banerjee et al. and rejected.
Regarding claim 13, claim 12 is obvious as described above. Claim 13 further recites the case wherein the subject has previously been treated with teduglutide at an adjusted dose.
Suzuki et al. discloses that: “In preclinical studies, glepaglutide (ZP1848) was shown to demonstrate greater intestinotrophic activity in the small intestine compared to the reference agent teduglutide. (97) In a model of small intestinal inflammation induced by indomethacin, glepaglutide was effective in reducing ulceration as well as inflammatory markers in tissue within the small intestine, (97,98) further supporting an anti-inflammatory and mucosal regenerative role for GLP-2.” (Suzuki et al., page 912, col. 1, para. 6).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to follow teduglutide treatment with glepaglutide treatment to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to use glepaglutide because Suzuki discloses that it has superior intestinotrophic activity compared to teduglutide and would have a reasonable expectation of success for the same reason.
Consequently, claim 13 is obvious over Suzuki et al. in view of Banerjee et al. and rejected.
Regarding claim 16, claim 16 recites a method of increasing intestinal mass and/or promoting or increasing longitudinal intestinal growth in a subject who has received an adjusted dose of teduglutide due to renal impairment, comprising administering ZP1848 or a pharmaceutically acceptable salt thereof to said subject, wherein no dose adjustment of ZP1848 or said salt is required.
Suzuki discloses the usage of ZP1848 for increasing intestinal regeneration and therefore mass:
“In preclinical studies, glepaglutide (ZP1848) was shown to demonstrate greater intestinotrophic activity in the small intestine compared to the reference agent teduglutide. (97) In a model of small intestinal inflammation induced by indomethacin, glepaglutide was effective in reducing ulceration as well as inflammatory markers in tissue within the small intestine, (97,98) further supporting an anti-inflammatory and mucosal regenerative role for GLP-2.” (Suzuki et al., page 912, col. 1, para. 6)
Suzuki does not disclose the case wherein the subject has previously received an adjusted dose of teduglutide due to renal impairment.
However, Banerjee et al. discloses that renal failure is commonly associated with short bowel syndrome: “Short bowel syndrome (SBS), defined as intestinal failure with a small bowel remnant length of less than ∼150 cm,1 describes a malabsorptive state caused by extensive loss of small intestinal length. The usual causes are listed in Table 1. With advances in medical and intensive care, the numbers of patients surviving these procedures are likely to increase. The chronic nephrological consequences of the short bowel syndrome, in patients with jejuno‐ileal bypass procedures, have been recently comprehensively reviewed in this journal.2
We now complete the spectrum of nephropathies by reporting the case histories of a series of patients presenting to our service with acute renal failure caused by the SBS, describing the range of metabolic disturbances associated with the condition, and making recommendations for treatment.” (Banerjee et al., page 2, para. 1).
Regarding the no dose adjustment element, the claim scope of claim 1 has been interpreted to include the first dose. No dose adjustment is possible on the first dose, since there is nothing to compare it to. Consequently, this element is present.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use ZP1848 as disclosed by Suzuki to increase intestinal mass a subject with renal failure as disclosed by Banerjee.
A person of ordinary skill in the art would be motivated to do use ZP1848 in this manner to increase the mass of the small intestine to help improve small intestine absorption. This improvement in absorption could help alleviate the issues associated with short bowel syndrome: “The major problems following established SBS are related to fluid/electrolyte imbalance, deficiencies in calcium, magnesium, zinc and vitamins A, D, E, K and B12, hypergastrinaemia, bile salt depletion, protein‐calorie malnutrition, pancreatic maldigestion and oxalate nephrolithiasis. Acute renal failure in our patients was predominantly due to salt and fluid depletion, and sepsis, particularly central catheter‐related sepsis in those receiving parenteral nutrition.” (Banerjee et al., page 6, para. 5). A person of ordinary skill in the art would follow teduglutide with glepaglutide due to the increased activity reported by Suzuki.
A person of ordinary skill in the art would have a reasonable expectation of success because Suzuki discloses that glepaglutide showed greater intestinotrophic activity compared to teduglutide. (Suzuki et al., page 912, col. 1, para. 6). Therefore, glepaglutide can increase the mass of the small intestine thereby boosting intestinal activity and helping to alleviate the problems described by Banerjee.
Consequently, claim 16 is obvious over Suzuki et al. in view of Banerjee et al. and rejected.
Regarding claim 17, claim 12 is obvious as described above. Claim 17 further recites the case wherein the subject has moderate renal impairment, severe renal impairment, or end stage renal disease (ESRD).
Banerjee et al. discloses that renal failure is commonly associated with short bowel syndrome: “Short bowel syndrome (SBS), defined as intestinal failure with a small bowel remnant length of less than ∼150 cm,1 describes a malabsorptive state caused by extensive loss of small intestinal length. The usual causes are listed in Table 1. With advances in medical and intensive care, the numbers of patients surviving these procedures are likely to increase. The chronic nephrological consequences of the short bowel syndrome, in patients with jejuno‐ileal bypass procedures, have been recently comprehensively reviewed in this journal.2
We now complete the spectrum of nephropathies by reporting the case histories of a series of patients presenting to our service with acute renal failure caused by the SBS, describing the range of metabolic disturbances associated with the condition, and making recommendations for treatment.” (Banerjee et al., page 2, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use ZP1848 as disclosed by Suzuki on a subject with renal failure caused by SBS as disclosed by Banerjee.
A person of ordinary skill in the art would be motivated to do use ZP1848 in this manner to reduce ulceration and inflammatory markers in the small intestine to help improve small intestine absorption. This improvement in absorption could help alleviate the issues associated with short bowel syndrome: “The major problems following established SBS are related to fluid/electrolyte imbalance, deficiencies in calcium, magnesium, zinc and vitamins A, D, E, K and B12, hypergastrinaemia, bile salt depletion, protein‐calorie malnutrition, pancreatic maldigestion and oxalate nephrolithiasis. Acute renal failure in our patients was predominantly due to salt and fluid depletion, and sepsis, particularly central catheter‐related sepsis in those receiving parenteral nutrition.” (Banerjee et al., page 6, para. 5).
A person of ordinary skill in the art would have a reasonable expectation of success because Suzuki discloses that glepaglutide showed greater intestinotrophic activity compared to teduglutide. (Suzuki et al., page 912, col. 1, para. 6). Therefore, glepaglutide can increase intestinal mass and thereby boost intestinal activity and help alleviate the problems described by Banerjee.
Consequently, claim 17 is obvious over Suzuki et al. in view of Banerjee et al. and rejected.
Regarding claim 18, claim 12 is obvious as described above. Claim 18 further recites the case wherein the condition is short bowel syndrome (SBS) in a subject optionally receiving parenteral support (PS).
Suzuki discloses the usage of ZP1848 for treating short bowel syndrome:
“Glepaglutide (ZP1848), first published in a patent application in 2006, (97) is a highly potent GLP-2 selective 39 amino acid peptide discovered by Zealand Pharma. (97) Zealand is looking to develop glepaglutide as a potential best in class GLP-2 treatment for patients with SBS.” (Suzuki et al., page 912, col. 1, para. 4).
Banerjee discloses that if enough small intestine is lost, parenteral support may be required: “Some 40–50% of small intestine can usually be lost without major metabolic or nutritional sequelae, however if more than 75% is lost, maintenance of nutritional status, at least initially, usually requires parenteral nutrition. Adaptive mechanisms, including intestinal dilatation and increases in crypt depth and villus height can lead to progressive recovery of the remaining bowel. The pattern of presentation of the SBS also depends on the site of intestinal resection (jejunal or ileal resection), the loss or preservation of the ileocaecal valve and large bowel and co‐existent small intestinal, liver or pancreatic disease.” (Banerjee et al., page 39, col. 1, para.72).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use ZP1848 as disclosed by Suzuki on a subject affected by SBS as disclosed by Banerjee that additionally needs parenteral support.
A person of ordinary skill in the art would be motivated to do use ZP1848 in this manner to reduce ulceration and inflammatory markers in the small intestine to help improve small intestine absorption. This improvement in absorption could help alleviate the issues associated with short bowel syndrome: “The major problems following established SBS are related to fluid/electrolyte imbalance, deficiencies in calcium, magnesium, zinc and vitamins A, D, E, K and B12, hypergastrinaemia, bile salt depletion, protein‐calorie malnutrition, pancreatic maldigestion and oxalate nephrolithiasis. Acute renal failure in our patients was predominantly due to salt and fluid depletion, and sepsis, particularly central catheter‐related sepsis in those receiving parenteral nutrition.” (Banerjee et al., page 6, para. 5).
A person of ordinary skill in the art would have a reasonable expectation of success because Suzuki discloses that glepaglutide showed greater intestinotrophic activity compared to teduglutide. (Suzuki et al., page 912, col. 1, para. 6). Therefore, glepaglutide can boost intestinal activity and help alleviate the problems described by Banerjee and reduce the need for parenteral support.
Consequently, claim 18 is obvious over Suzuki et al. in view of Banerjee et al. and rejected.
Regarding claim 20, claim 18 is obvious as described above. Claim 20 further recites the case wherein said dosing regime is a once or twice weekly dosing regime. Neither Suzuki nor Banerjee specifically recite such a dosing regime.
However, Suzuki does disclose the potential for a weekly dosing regime: “Glepaglutide offers a more convenient dosing form via a ready-to-use autoinjector device, which removes the requirement for reconstitution from lyophilized powder. In human clinical studies, glepaglutide demonstrates favorable pharmacokinetics and trials were conducted in 2017 to investigate the potential for up to weekly dosing.” (Suzuki et al., page 912, col. 1, para. 8).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to arrive at the claimed dosing regime. Starting with the weekly potential dosing described by Suzuki, it would have been a matter of routine optimization to arrive at the claimed dosing regime.
MPEP 2144.05(II)(A) states: “It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art.").”
Consequently, claim 20 is obvious over Suzuki et al. in view of Banerjee et al. and rejected.
Regarding claim 21, claim 1 is obvious as described above. Claim 21 further recites the case wherein each unadjusted dose is between 1 mg and 20 mg, e.g. between 5 mg and 15 mg, between 7 mg and 12 mg, or between 9 mg and 11 mg.
Suzuki discloses: “At all doses tested (0.1, 1, 10 mg) the drug was reported to be safe and well tolerated.” (Suzuki et al., page 912, col. 2, para. 1).
The 10 mg dosage disclosed by Suzuki anticipates the recited ranges of claim 21.
Consequently, claim 21 is obvious over Suzuki et al. in view of Banerjee et al. and rejected.
Regarding claim 22, claim 21 is obvious as described above. Claim 22 further recites the case wherein each individual dose is about 10 mg.
Suzuki discloses: “At all doses tested (0.1, 1, 10 mg) the drug was reported to be safe and well tolerated.” (Suzuki et al., page 912, col. 2, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to try each of the recited dosages in Suzuki. Since one of these doses is 10 mg, this reads on the limitations of claim 22.
Consequently, claim 21 is obvious over Suzuki et al. in view of Banerjee et al. and rejected.
Regarding claim 27, claim 23 is anticipated as described above. Claim 27 recites the case wherein the kit further comprises one or more chemotherapeutic agents.
Suzuki discloses the usage of GLP-2 agonists in conjunction with chemotherapeutics:
“GLP-2 Peptide Agonists in Chemotherapy Induced Diarrhea
Gastrointestinal toxicity is a common dose limiting side effect associated with cancer therapy and poses a significant burden on the patient’s quality of life. Chemotherapy induced diarrhea (CID) is experienced in a large proportion of patients receiving 5-fluorouracil (5-FU) as single agent or in combination therapy and can lead to life threatening complications that require vigilant monitoring and aggressive therapy. (108)5-FU based therapies cause toxic effects to the GI epithelium, causing inflammation, ulcerations, and atrophy in the GI mucosa, contributing to clinical symptoms (e.g., pain and severe diarrhea) that can limit the dose and duration of cancer therapy. Effective therapies that protect against such damage and promote mucosal recovery are needed for better management of GI complications associated with chemotherapy.” (Suzuki et al., page 913, col. 1., para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the method of Suzuki and Banerjee in combination with chemotherapeutic agents to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to make this combination because the chemotherapies described by Suzuki cause intestinal distress and damage that can be treated by the method of Suzuki and Banerjee.
A person of ordinary skill in the art would have a reasonable expectation of success because glepaglutide is known to help repair the small intestine: “In preclinical studies, glepaglutide (ZP1848) was shown to demonstrate greater intestinotrophic activity in the small intestine compared to the reference agent teduglutide. (97) In a model of small intestinal inflammation induced by indomethacin, glepaglutide was effective in reducing ulceration as well as inflammatory markers in tissue within the small intestine, (97,98) further supporting an anti-inflammatory and mucosal regenerative role for GLP-2.” (Suzuki et al., page 912, col. 1, para. 6)
Consequently, claim 27 is obvious over Suzuki et al. in view of Banerjee et al. and rejected.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Suzuki et al. (Suzuki, et al. Journal of medicinal chemistry 63.3: 905-927 (2019)) in view of Chaudhari et al. (Chaudhari, et al.. Int J Adv Pharm Biol Chem 1.1: 21-34 (2012)).
Regarding claim 24, claim 23 is anticipated as described above. Suzuki does not explicitly disclose a carrier or excipient.
However, Chaudhari et al. discloses the uses and benefits of pharmaceutical carriers:
“Many dosage forms formulated today are complex system containing many other components along with the active pharmaceutical ingredient (API); these compounds are generally added along with the active pharmaceutical ingredients in order to: Protect, support or enhance stability of the formulation:- Most of the times it is observed that the active pharmaceutical ingredient in its pure form does not retain its stability for long which results in its
denaturation, or sticking to the container wall thus rendering it unfit, hence in order to stabilize the API excipients are added which aid in maintaining the stability of the product and ensures that API retains its stability for a considerable period of time thus improving the shelf life of dosage formulation.” (Chaudhari et al, page 21, col. 1, para. 1).
Chaudhari also discloses a wide range of excipients in Table 1 and Table 2 along with advantages of each excipient (Chaudhari, et al, page 28-29, Table 1, Table 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the kit of Suzuki with the pharmaceutically acceptable excipients of Chaudhari to arrive at the claimed invention. A person of ordinary skill in the art would be motivated by the advantages disclosed by Chaudhari and have a reasonable expectation of success due to the frequency of use of such excipients.
Consequently, claim 24 is obvious over Suzuki et al. in view of Chaudhari et al. and rejected.
Conclusion
No claim is allowed
Claims 1, 6-13, 16-18, and 20-27 are objected to.
Claims 1, 6-13, 16-18, and 20-27 are rejected.
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/DAVID PAUL BOWLES/ Examiner, Art Unit 1654
/LIANKO G GARYU/ Supervisory Patent Examiner, Art Unit 1654