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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 December 23, 2025, has been entered.
Priority
Receipt is acknowledged of certified copies of KR10-2020-0040944.
Applicant cannot rely upon the certified copy of the foreign priority application to overcome prior art rejections because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
The earliest effective filing date of claims 1-18 is April 2, 2021.
Claim Rejections - 35 USC § 103
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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, 3-6, 8-12, and 15-19 are rejected under 35 U.S.C. 103 as being unpatentable over Mayo et al. (NPL 3; IDS 5/10/2024) in view of Choi et al. (WO 2019/066586 A1, published 4 April 2019; English language equivalent US 2020/0262888 A1), Sung et al. (US 2017/0362293 A1), and Giorgino et al. (US 2016/0067311 A1).
Determining the scope and contents of the prior art.
Mayo et al. teach a method of preventing or treating cancer chemotherapy-induced mucositis in a subject in need thereof comprising administering a therapeutically effective amount of a GLP-2 derivative (Table 1). Mayo et al. teach that subjects are pre- and post-treated with a GLP-2 analogue (p. 237, col 2, para 2). Mayo et al. teach GLP-2 treatment results in an increase in whole body weight and in intestinal wet weight, and in a number of improved intestinal histological parameters including crypt depth, villous height, crypt cell proliferation and crypt cell apoptosis, when compared with saline (p. 237, col 2, para 2).
Ascertaining the differences between the prior art and the claims at issue.
Mayo et al. do not teach that the GLP-2 derivative is of Chemical Formula I or is linked to an immunoglobin Fc domain.
Resolving the level of ordinary skill in the pertinent art.
The substituted GLP-2 derivatives and their functions were known in the prior art. Choi et al. teach the use of GLP-2 analogues for the treatment of intestinal disease including mucositis (para [0067]). Specifically, Choi et al. teach the long-acting conjugate of CA-GLP-2 RC (10K PEG) derivative (CA-GLP-2 KC-PEG(10K)-immunoglobulin Fc) and the long-acting conjugate of CA-GLP-2 RC (10K PEG) derivative (CA-GLP-2 RC-PEG(10K)-immunoglobulin Fc), in which the CA-GLP-2 KC or CA-GLP-2 RC is covalently linked to the immunoglobulin Fc by the PEG (Example 1). These derivatives are species of claimed Chemical Formula 1 wherein X is the GLP-2 derivative, L is the PEG(10K), and F is the immunoglobulin Fc.
Choi et al. teach that the GLP-2 derivative comprises an amino acid sequence of General Formula 1:
X1X2DGSFSDEMNTILDNLAARDFINWLIQTX30ITDX34,
wherein
X1 is histidine, imidazoacetyldeshistidine, desaminohistidine, β-hydroxyimidazopropionyldeshistidine, N-dimethylhistidine, or β-carboxyimidazopropionyldeshistidine;
X2 is alanine, glycine, or 2-aminoisobutyric acid (Aib);
X30 is lysine or arginine; and
X34 lysine, arginine, glutamine, histidine, 6-azido-lysine, or cysteine; with the proviso that any sequence identical to an amino acid sequence of SEQ ID NO: 1 in General Formula 1 is excluded (para [0039]-[0044]).
The long-acting GLP-2 derivatives of Choi et al. meet the structural requirements of claim 1.
Choi et al. teach that the GLP-2 derivatives wherein
X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is cysteine;
X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is lysine;
X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is arginine, and X34 is lysine;
X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is 6-azido-lysine;
X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is arginine, and X34 is cysteine;
X1 is imidazoacetyldeshistidine, X2 is Aib, X30 is lysine, and X34 is cysteine; or
X1 is histidine, X2 is Aib, X30 is lysine, and X34 is cysteine (para [0047]-[0053]), which are identical to the GLP-2 derivatives recited in instant claim 3.
Choi et al. teach that the GLP-2 derivative is an amino acid sequence selected from the group consisting of SEQ ID NOS: 2 to 8 (Table 1), which are identical to the GLP-2 derivatives recited in instant claims 4 and 19.
Choi et al. teach the GLP-2 derivative may be amidated (para [0206]), as required by instant claim 5.
Choi et al. teach that the Fc region is non-glycosylated (para [0036]), as required by instant claim 15 or a dimer (para [0199]), as required by instant claim 16.
Choi et al teach that L is polyethylene glycol (Example 1), satisfying instant claim 17.
Choi et al. teach that the molecular weight of L is 10kDa (Example 1), which falls within the range recited in instant claim 18.
In addition, the use of other long-acting GLP-2 derivatives to treat chemotherapy-induced mucositis has been reported in the prior art. For example, Sung et al. teach that a structurally distinct, long-acting GLP-2-Fc conjugate can prevent diarrhea caused by irinotecan in a mouse model (Example 3-10). Sung et al. teach in para. [0154] and Figure 16 that the group treated with the GLP-2-Fc conjugate showed a decrease in diarrhea score compared to the untreated group. In addition, Giorgino et al. teach that the GLP-2 derivative elsiglutide was effective at preventing chemotherapy-induced diarrhea (CID) in clinical trials for patients with colorectal cancer receiving 5-FU based chemotherapy (Example 2). Giorgino et al. teach in para. [0017] that the occurrence of CID is prevented or its severity is reduced by elsiglutide and that the elsiglutide provides a protective effect against CID that extends long after the elsiglutide is administered.
It would have been obvious to one of ordinary skill in the art at the time the invention was filed to substitute the GLP-2 derivatives in the method of treating cancer chemotherapy-induced mucositis taught by Mayo et al. with the GLP-2 derivatives taught by Choi et al. The rationale for obviousness is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention (MPEP § 2143.01(G)). The relevant findings for this rationale are as follows.
(1) There was some teaching, suggestion, or motivation, either in the references themselves or in the knowledge generally available to one of ordinary skill in the art, to modify the reference or to combine reference teachings.
Mayo et al. identify short in vivo half-life as a limitation for GLP-2 drugs (emphasis added, citations removed; p. 237, col. 1, para. 1):
Normal actions of GLP-2, which act on GLP-2 receptors that are specifically located in the GIT, include aiding nutrient absorption via altering expression and activity of nutrient transporters, reducing GIT motility and intestinal epithelial permeability. These are vital actions of the peptide. Interestingly, however, GLP-2 is also known to stimulate crypt cell proliferation, increasing mucosal epithelium thickness in both the small and large intestines, whilst inducing anti-apoptotic pathways and increasing blood flow to select areas of the GIT. Naturally occurring GLP-2 is rapid acting and has a short half- life of only 7 min before degradation and metabolism. The metabolism of GLP-2 occurs via the enzyme dipeptidyl peptidase-IV (DPP-IV), which truncates the protein to its biologically inactive form by degradation from the N-terminus at the alanine in position 2. DPP-IV is abundant in the intestinal mucosa, potentially affecting the function of GLP- 2 before it enters circulation. The function of DPP-IV is very specific, and any changes to the N-terminus amino acids will alter the activity of DPP-IV and increase time before degradation and metabolism of this regulatory peptide. Research demonstrating the role of DPP-IV has shown that a deficiency of this enzyme in rats caused an increase in biologically active GLP-2 and an increased bowel weight.
Therefore, the primary reference Mayo et al. establishes that short in vivo half-life is a problem associated with the use of GLP-2 to treat gastrointestinal mucositis caused by cancer chemotherapy.
Choi et al. also teach that short in vivo half-life is a problem with GLP-2 as drug:
[0004] However, GLP-2 still has limitations in being developed into a commercial drug. Peptides such as GLP-2 can be easily denatured due to low stability, loses activity due to degradation by protease in the body, and are easily removed through the kidney due to their relatively small size. Therefore, in order to maintain optimal blood concentrations and titers of peptide drugs, there is a need to administer the peptide drug more frequently. However, most peptide drugs are administered in various types of injections, and frequent injections are required to maintain the blood concentration of the peptide drug, which causes severe pain in patients. In this regard, there have been many attempts to solve these problems, one of which has developed a method of increasing membrane permeability of a peptide drug, leading to the delivery of the peptide drug to the body by inhalation through an oral or a nasal. However, this method has a limitation of a low delivery efficiency of the peptide drug as compared with the injection thereof, and thus it still remains difficult to retain sufficient biological activity of the peptide drug for therapeutic use.
[0005] In particular, GLP-2 has extremely short in vivo half-life (7 minutes or shorter) due to its inactivation by dipeptidyl peptidase-IV (DPP IV) which cleaves between the amino acids at position 2 (Ala) and position 3 (Asp) of GLP-2
Choi et al. developed a solution to this problem, the conjugation of GLP-2 peptides to immunoglobulin Fc regions via PEG linkers. Choi et al. report the following advantageous effects of the long-acting GLP-2 conjugates:
[0073] Since the GLP-2 derivative and long-acting conjugate thereof of the present invention have a significantly high activity and a superior in vivo duration effect, these can be effectively used for the prevention, amelioration, and treatment of intestinal disease, intestinal injury, and gastrosia.
Here Choi et al. explicitly motivate one of ordinary skill in the art to use the long-acting conjugates in place of standard GLP-2 therapies for treating and preventing intestinal disease because doing so overcomes the art-recognized problem of short in vivo half-life.
One of ordinary skill in the art would understand the problem identified by Mayo et al., short in in vivo half-life of GLP-2 in an otherwise promising therapy for cancer chemotherapy-induced gastrointestinal mucositis based on the express teaching in that reference. One of ordinary skill in the art would recognize that Choi et al. provides a solution to the problem of short in in vivo half-life of GLP-2, based on the express teaching and evidence in that reference. One of ordinary skill in the art would be motivated to combine the references in order to use a solution in the prior art of Choi et al. to solve a problem identified in the prior art of Mayo et al.
Therefore, there was some teaching, suggestion, or motivation, either in the references themselves or in the knowledge generally available to one of ordinary skill in the art, to modify the reference or to combine reference teachings.
(2) There was reasonable expectation of success.
In addition to describing short in vivo half-life as a problem for treating cancer chemotherapy-induced gastrointestinal mucositis with GLP-2 peptides, Mayo et al. explicitly state that a long-acting GLP-2 derivative would improve treatment (p. 245, col. 1):
Analogues of GLP-2, which are longer-lasting and exert a potent effect on the GIT, are of particular interest, due to the likely benefits of potentially fast-tracking repair caused by chemotherapeutic agents like irinotecan.
This assertion is supported by Giorgino et al. which teaches that the long-acting GLP-2 derivative
elsiglutide was effective at preventing chemotherapy-induced diarrhea (CID) in clinical trials for patients with colorectal cancer receiving 5-FU based chemotherapy (Example 2). Giorgino et al. teach in para. [0017] that the occurrence of CID is prevented or its severity is reduced by elsiglutide and that the elsiglutide provides a protective effect against CID that extends long after the elsiglutide is administered.
In addition, Choi et al. provide evidence that the substitution would be beneficial. In Example 6, Choi et al. present a comparison between the GLP-2 conjugated to an Fc region and an unconjugated GLP-2 teduglutide. The data establish that both AUC and half-life of the long-acting conjugate of CA GLP-2 RK derivative were significantly increased compared to those of Teduglutide (¶ [0289], Figure 3, Table 4).
Therefore, one of ordinary skill in the art would predict that a long-acting GLP-2 of Choi et al. could be used to treat gastrointestinal mucositis caused by chemotherapy using anticancer drugs.
(3) Whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness.
Example 3 demonstrates that a claimed GLP-2 conjugate caused significantly less weight loss of the small intestine in a mucositis model induced by chemotherapy and significantly greater weight gain of the small intestine during recovery compared to an unconjugated derivative taught in the prior art, teduglutide.
MPEP § 716.02(c)(II) states: "Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967)
In the instant case, the beneficial results evidenced in Example 3 of the specification are expected in view of the prior art.
First, Mayo et al. establish that GLP-2 derivatives with increased half-lives are expected to be effective at treating mucositis caused by chemotherapy (emphasis added, citations removed; p. 237, col. 1., para. 2 – col. 2, para. 1):
Following evidence that naturally occurring GLP-2 alters GI functions and can improve GI damage, pharmaceutical companies have begun to develop degradation- resistant forms of the peptide. Analogues of GLP-2 are being created with a change in amino acids at the N-terminus cleavage site to increase effect on the GI tract. These analogues, which increase the peptide biological function and half-life, have been suggested for use in improving diseases that severely damage the GI tract and alter its function. Teduglutide, a GLP-2 analogue which has an increased enzymatic degradation resistance of 2–3 h, has been implicated in improving a number of debilitating GI diseases, including short bowel syndrome (SBS), Crohn’s disease and ulcerative colitis, which are common inflammatory bowel diseases (IBDs) and share similar characteristics to GI mucositis.
The promising results of teduglutide and other GLP-2 analogues in these models of GI disease have sparked studies into their potential effects on GI mucositis. GLP-2 analogues, including teduglutide, have been used in models of chemotherapy-, targeted therapy- and radiotherapy-induced GI mucositis (Table 1). So far, studies have been examined rodent models with administered chemotherapeutic agents, targeted therapies or radiotherapy, which were also pre- and post-treated with a GLP- 2 analogue until animals were killed. These studies showed increased whole body weight, intestinal wet weight and a number of improved intestinal histological parameters including crypt depth, villous height, crypt cell proliferation and decreased crypt cell apoptosis, when compared with saline-treated rodents.
In summary, Mayo et al. teach that teduglutide was an early attempt to improve GLP-2 by increasing its half-life and that this GLP-2 analogue is effective in animal models of chemotherapy-, targeted therapy- and radiotherapy-induced GI mucositis.
Choi et al. provide a comparison to the teduglutide and demonstrate that the GLP-2 analogues conjugated to immunoglobulin Fc regions via PEG linkers have an improved in vivo half-life and an improved effect on intestinal weight in mice (¶ [0292], emphasis added):
As a result, in both Teduglutide and the long-acting conjugate of CA GLP-2 RK derivative, the weight of the small intestines was increased in a dose-dependent manner (FIG. 4(A)), and it could be derived that the increase of the weight of the small intestines is due to the increase in the length of the villi based on the fact that the increase of the intestinal weight is associated with the increase in the villi length (FIG. 4(B)). The high- dose administration group (15 nmol/kg/BID), which is known to exhibit the maximum efficacy of Teduglutide, was similar to the low-dose administration group (4.15 nmol/kg/Q2D) of the group administering the long-acting conjugate of the CA GLP-2 RK derivative, and it was confirmed that the long-acting conjugate of the CA GLP-2 RK derivative had an effect exceeding the maximum efficacy of Teduglutide in a dose- dependent manner. The result thereof is shown in FIG. 4(A) and FIG. 4(B).
Thus, the prior art of Choi et al. suggests that increasing in vivo half-life of GLP-2 leads to an increase in the therapeutic effect of the GLP-2. It follows then that the long-acting conjugates of Choi et al. would have an increase in therapeutic effect in the animal models of chemotherapy-, targeted therapy- and radiotherapy-induced GI mucositis taught by Mayo et al.
The results shown in Example 3 are consistent with this prediction based on the prior art of Mayo et al. and Choi et al. Therefore, the results in Example may be beneficial but they are expected beneficial results not unexpected beneficial results.
The rationale to support a conclusion that the claim would have been obvious is that "a person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006). Therefore, claims 1, 4-5, and 15-19 are obvious over the cited art.
With respect to claim 6, Mayo et al. teach gastrointestinal mucositis (Table 1).
With respect to claims 8-10, Mayo et al. teach 5-FU and Irinotecin (Table 1).
With respect to claim 11, Mayo et al. teach that subjects are pre- and post-treated with a GLP-2 analogue (p. 237, col 2, para 2).
With respect to claim 12, Mayo et al. teach GLP2 treatment showed increased whole body weight, intestinal wet weight and a number of improved intestinal histological parameters including crypt depth, villous height, crypt cell proliferation and decreased crypt cell apoptosis, when compared with saline (p. 237, col 2, para 2).
Response to Arguments
Applicant's arguments filed December 23, 2025, have been fully considered but they are not persuasive.
Applicant traverses the rejection on the grounds that the prior art of Mayo et al. and Choi et al. fails to disclose the “core technical feature” of the claims: anti-inflammatory, immunoregulatory activity with a direct therapeutic effect on chemotherapy-induced mucositis. Applicant argues that Choi et al. discloses nutritional effects on intestinal structure rather than anti-inflammatory effects, and that Mayo et al. do not teach the claimed GLP-2 derivatives at all and therefore cannot teach the anti-inflammatory effect. Applicant argues that chemotherapy-induced mucositis is an acute inflammatory condition that requires anti-inflammatory activity to treat.
In response to applicant's argument that the prior art fails to disclose the core technical feature of the claims, the fact that the inventor 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. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). In the instant case, the prior art of Mayo et al. explicitly teaches using GLP-2 to treat chemotherapy-induced mucositis and teaches that doing so could be improved by using a long-acting GLP-2 derivative. Choi et al. teaches a long-acting GLP-2 derivative. Therefore, there is ample motivation from the prior art to use the GLP-2 derivatives of Choi et al. in the method of treating chemotherapy-induced mucositis with GLP-2 taught by Mayo et al. Any effects on inflammation and the mechanism of action would occur as a result of practicing the precise method suggested by the prior art.
Even so, Mayo et al. does teach that GLP-2 can have an anti-inflammatory effect and acknowledges that chemotherapy-induced mucositis is an inflammatory condition. See section titled “Intestinal permeability, the intestinal microbiome and inflammatory pathways” beginning on p. 242. In addition, Mayo et al. teach that GLP-2s have anti-inflammatory action (p. 237, col 2; emphasis added, citations removed):
Studies using teduglutide in rodent models of IBD, including Crohn’s disease and colitis, have shown promising results (leading to a clinical trial in Crohn’s disease), with increased mucosal area, mucosal integrity, improved small and large bowel weights and decreased inflammatory response in mice receiving teduglutide when compared with those only receiving saline
These studies showed increased whole body weight, intestinal wet weight and a number of improved intestinal histological parameters including crypt depth, villous height, crypt cell proliferation and decreased crypt cell apoptosis, when compared with saline-treated rodents. Studies by Boushey et al. have shown that the reduction of apoptosis was caused specifically through caspase-3 and caspase-8 signaling. In addition, Kissow et al. found that there was a significant decrease in the influx of myeloperoxidase-positive cells, a marker of inflammation, in GLP-2 analogue-treated animals.
Given that Mayo et al. teaches that GLP-2 has anti-inflammatory properties and that at least the long-acting derivative teduglutide does as well, one of ordinary skill in the art would expect success in applying GLP-2 to the treatment of chemotherapy-induced mucositis. In fact, Mayo et al. explicitly states on p. 237, col 2:
This decrease indicates that GLP-2 analogues may potentially alter the effects of cancer agents on not only pathways of proliferation and apoptosis, but inflammatory pathways, which are responsible for a substantial amount of the damage seen in GI mucositis.
This teaching by Mayo et al. contradicts Applicant’s argument that the core technical effect of the invention is not taught in the prior art.
In addition, Sung et al. confirm that a fusion polypeptide including a GLP-2 and an immunoglobulin Fc polypeptide exhibits anti-inflammatory activity (Example 3-6). Sung et al. report in para. [0145]:
GLP-2-hyFc9 fusion protein showed an activity of 98% thus showing no reduction in its inflammation-related biological activity, even after the fusion with hyFc9.
Sung et al. demonstrate that this same conjugate is effective in a mouse model for chemotherapy-induced mucositis (Example 3-10). Given that Sung et al. teaches that an GLP-2-Fc conjugate has anti-inflammatory properties and reduces chemotherapy-induced diarrhea, one of ordinary skill in the art would expect success in applying GLP-2 to the treatment of chemotherapy-induced mucositis.
Next, Applicant argues that Han et al. show that it is common for activity to be reduced when a peptide in conjugated with a polymer and that therefore one of ordinary skill in the art would not predict that modifying a GLP-2 derivative into conjugate form would maintain or improve therapeutic effect on chemotherapy-induced mucositis. This argument is not persuasive. Han et al. does not disclose any teaching that is relevant specifically to GLP-2, to the conjugates of Choi et al., or to the treatment of chemotherapy-induced mucositis. Rather, Han et al. is directed to modification of interferon alpha-2a with polyethylene glycol or zwitterionic polymers (abstract).
In contrast, there is a specific, relevant evidence found in Choi et al. discussed above and reiterated here. Choi et al. provide a comparison to the teduglutide and demonstrate that the GLP-2 analogues conjugated to immunoglobulin Fc regions via PEG linkers have an improved in vivo half-life and an improved effect on intestinal weight in mice (¶ [0292], emphasis added):
As a result, in both Teduglutide and the long-acting conjugate of CA GLP-2 RK derivative, the weight of the small intestines was increased in a dose-dependent manner (FIG. 4(A)), and it could be derived that the increase of the weight of the small intestines is due to the increase in the length of the villi based on the fact that the increase of the intestinal weight is associated with the increase in the villi length (FIG. 4(B)). The high- dose administration group (15 nmol/kg/BID), which is known to exhibit the maximum efficacy of Teduglutide, was similar to the low-dose administration group (4.15 nmol/kg/Q2D) of the group administering the long-acting conjugate of the CA GLP-2 RK derivative, and it was confirmed that the long-acting conjugate of the CA GLP-2 RK derivative had an effect exceeding the maximum efficacy of Teduglutide in a dose-dependent manner. The result thereof is shown in FIG. 4(A) and FIG. 4(B).
Thus, the prior art of Choi et al. suggests that increasing in vivo half-life of GLP-2 by addition of a large, Fc conjuagte leads to an increase in the therapeutic effect of the GLP-2. It follows then that the long-acting conjugates of Choi et al. would have an increase in therapeutic effect in the animal models of chemotherapy-, targeted therapy- and radiotherapy-induced GI mucositis taught by Mayo et al. This expectation is further corroborated by the data in Sung et al. discussed above. When weighed against the specific teaching in Mayo et al. and Giorgino et al. to use GLP-2, including long-acting derivatives, to treat chemotherapy-induced mucositis, the motivation to use a long-acting derivative such as that by Choi et al. to solve an art-recognized problem of short in vivo half-life, and the evidence in Choi et al., the general teaching in Han et al. is insufficient to overcome the prima facie case.
For these reasons, the rejection is maintained.
Claims 1, 3-6, 8-12, and 15-19 are rejected under 35 U.S.C. 103 as being unpatentable over Sung et al. (US 2017/0362293 A1) in view of Choi et al. (WO 2019/066586 A1, published 4 April 2019; English language equivalent US 2020/0262888 A1).
Determining the scope and contents of the prior art.
Sung et al. teach a method of treating gastrointestinal mucositis caused by cancer chemotherapy comprising administering a effective amount of a long-acting fusion protein with increased in vivo half-life comprising GLP-2 and an immunoglobulin Fc region (para. [0038], [0039], [0052], [0053], [0057]-[0059], [0093], [0096], [0154]).
Sung et al. teach that the fusion proteins solve a known problem with GLP-2, low in vivo half-life, by fusion to an immunoglobulin Fc polypeptide (para. [0038]). Sung et al. teach GLP-2-hyFc9, which includes an IgD hinge region consisting of a 40 amino acid sequence (Figure 3, para. [0039], [0052]). Sung et al. teach that GLP-2-hyFc9 has an increased half-life (Examples 2 to 4). Sung et al. teach that GLP-2-hyFc9 does not reduce cAMP activity, which can reduce inflammation (Figure 12), and was shown to have excellent effects of reducing diarrhea and lethality caused by cancer chemotherapy (Figures 16 and 17) (para. [0053]).
Sung et al. teach that a long-acting GLP-2-Fc fusion protein can prevent diarrhea caused by irinotecan in a mouse model (Example 3-10). Sung et al. teach in para. [0154] and Figure 16 that the group treated with the GLP-2-Fc fusion protein showed a decrease in diarrhea score compared to the untreated group.
In addition, Sung et al. teach that the long-acting GLP-2 fusion proteins can be used to treat mucositis caused by anticancer chemotherapy without limitation as long as the chemotherapy can induce endoenteritis or diarrhea, e.g., 5-fluorouracil (5-FU), irinotecan, leucovorin, oxaliplatin, etc. (para. [0059]).
Sung et al. reduced to practice an animal model (Example 3-10):
Irinotecan or 5-FU, among the anticancer chemotherapy drugs used for killing cancer cells, can induce villous atrophy by destroying crypts cells, which form the villi of intestinal cells, and this may lead to fatal diarrhea. Since the villous atrophy and diarrhea induced by anticancer chemotherapy drugs may affect lethality, an experiment was performed to confirm whether the GLP-2-hyFc9 treatment can prevent diarrhea and lethality induced by anticancer chemotherapy drugs. Male Sprague Dawley rats (15 rats/group) were treated with 5-FU once daily to a total of four times at a concentration of 75 mg/kg to induce diarrhea. The rats were treated with GLP-2- hyFc a total of four times at a concentration of 80 nmol/kg/day or once at a concentration of 320 nmol/kg/day, and diarrhea score was examined for 10 days, thereby confirming lethality. As a result, as shown in FIG. 16, the group treated four times with GLP-2-hyFc9 at a concentration of 80 nmol/kg/day showed a decrease in diarrhea score compared to the untreated group, and the group treated once with GLP-2-hyFc9 at a concentration of 320 nmol/kg/day showed a significant decrease in diarrhea score compared to the group treated four times with GLP-2- hyFc9 at a low dose. Additionally, the lethality induced by 5-FU (27%) was reduced by 20% to 6.7% in the group treated with GLP-2-hyFc9 (FIG. 17). Therefore, it was confirmed that GLP-2- hyFc9 has the effect of preventing diarrhea induced by anticancer chemotherapy.
Ascertaining the differences between the prior art and the claims at issue.
Sung et al. do not teach that the long-acting GLP-2-Fc fusion protein is of Chemical Formula I. Sung et al. teaches a fusion polypeptide rather than a conjugate comprising a ethylene glycol repeating unit linker between the GLP-2 and Fc.
Resolving the level of ordinary skill in the pertinent art.
The substituted GLP-2 derivatives and their functions were known in the prior art. Choi et al. teach the use of GLP-2 analogues for the treatment of intestinal disease including mucositis (para [0067]). Specifically, Choi et al. teach the long-acting conjugate of CA-GLP-2 RC (10K PEG) derivative (CA-GLP-2 KC-PEG(10K)-immunoglobulin Fc) and the long-acting conjugate of CA-GLP-2 RC (10K PEG) derivative (CA-GLP-2 RC-PEG(10K)-immunoglobulin Fc), in which the CA-GLP-2 KC or CA-GLP-2 RC is covalently linked to the immunoglobulin Fc by the PEG (Example 1). These derivatives are species of claimed Chemical Formula 1 wherein X is the GLP-2 derivative, L is the PEG(10K), and F is the immunoglobulin Fc.
Choi et al. teach that the GLP-2 derivative comprises an amino acid sequence of General Formula 1:
X1X2DGSFSDEMNTILDNLAARDFINWLIQTX30ITDX34,
wherein
X1 is histidine, imidazoacetyldeshistidine, desaminohistidine, β-hydroxyimidazopropionyldeshistidine, N-dimethylhistidine, or β-carboxyimidazopropionyldeshistidine;
X2 is alanine, glycine, or 2-aminoisobutyric acid (Aib);
X30 is lysine or arginine; and
X34 lysine, arginine, glutamine, histidine, 6-azido-lysine, or cysteine; with the proviso that any sequence identical to an amino acid sequence of SEQ ID NO: 1 in General Formula 1 is excluded (para [0039]-[0044]).
The long-acting GLP-2 derivatives of Choi et al. meet the structural requirements of claim 1.
Choi et al. teach that the GLP-2 derivatives wherein
X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is cysteine;
X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is lysine;
X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is arginine, and X34 is lysine;
X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is 6-azido-lysine;
X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is arginine, and X34 is cysteine;
X1 is imidazoacetyldeshistidine, X2 is Aib, X30 is lysine, and X34 is cysteine; or
X1 is histidine, X2 is Aib, X30 is lysine, and X34 is cysteine (para [0047]-[0053]), which are identical to the GLP-2 derivatives recited in instant claim 3.
Choi et al. teach that the GLP-2 derivative is an amino acid sequence selected from the group consisting of SEQ ID NOS: 2 to 8 (Table 1), which are identical to the GLP-2 derivatives recited in instant claims 4 and 19.
Choi et al. teach the GLP-2 derivative may be amidated (para [0206]), as required by instant claim 5.
Choi et al. teach that the Fc region is non-glycosylated (para [0036]), as required by instant claim 15 or a dimer (para [0199]), as required by instant claim 16.
Choi et al teach that L is polyethylene glycol (Example 1), satisfying instant claim 17.
Choi et al. teach that the molecular weight of L is 10kDa (Example 1), which falls within the range recited in instant claim 18.
It would have been obvious to one of ordinary skill in the art at the time the invention was filed to substitute the GLP-2-Fc fusion protein in the method of treating cancer chemotherapy-induced mucositis taught by Sung et al. with the GLP-2 derivatives taught by Choi et al. The rationale for obviousness is simple substitution of one known element for another to obtain predictable results (MPEP § 2143.01(B)). The relevant findings for this rationale are as follows.
(1) The prior art contained a device (method, product, etc.) which differed from the claimed device by the substitution of some components (step, element, etc.) with other components. In the instant case, the primary reference teaches a method of treating cancer chemotherapy-induced mucositis with a long-acting GLP-2-Fc fusion protein which differs from the claimed method by the substitution of a GLP-2 of Chemical Formula 1 for the GLP-2-Fc fusion protein. Therefore, the prior art contained a device (method, product, etc.) which differed from the claimed device by the substitution of some components (step, element, etc.) with other components.
(2) The substituted components and their functions were known in the art. Choi et al. teach GLP-2 compounds of Chemical Formula 1, which is the substituted component. The function of GLP-2 compounds of Chemical Formula 1 is known in the art because Choi et al. teach in para. [0073] that:
Since the GLP-2 derivative and long-acting conjugate thereof of the present invention have a significantly high activity and a superior in vivo duration effect, these can be effectively used for the prevention, amelioration, and treatment of intestinal disease, intestinal injury, and gastrosia.
Therefore, the substituted components and their functions were known in the art.
(3) One of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable. One of ordinary skill in the art would expect that the GLP-2 compounds of Chemical Formula 1 performs the function of treating chemotherapy-induced mucositis in the combination because 1) Sung et al. teach that fusion protein comprising GLP-2 and immunoglobulin Fc regions can be used for this purpose and that Choi et al. teach that the GLP-2 conjugated to immunoglobulin Fc regions of Chemical Formula 1 have biological activity suitable for treating intestinal diseases. Therefore, one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable.
(4) Whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness. The examples in the specification are consistent with the teaching of Sung et al. and Choi et al. and therefore do not constitute unexpected results.
The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art. Therefore, claims 1, 4-5, and 15-19 are obvious over the cited art.
With respect to claims 6 and 8-10, Sung et al. teach that treatment of mucositis caused by anticancer chemotherapy without limitation as long as the chemotherapy can induce endoenteritis or diarrhea, e.g., 5-fluorouracil (5-FU), irinotecan, leucovorin, oxaliplatin, etc. (para. [0059], Example 3-10).
With respect to claim 11, Sung et al. teach post-treatment with GLP-2-hyFc a total of four times at a concentration of 80 nmol/kg/day or once at a concentration of 320 nmol/kg/day (Example 3-10). It would have been obvious to optimize the timing of administration through routine experimentation.
With respect to claim 12, Choi et al. teach that GLP-2 compounds of Chemical Formula 1 decrease the weight of the small intestines in a dose-dependent manner (para. [0292]).
Conclusion
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/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654