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
This application, filed on 02/28/2024, is a continuation of U.S. Application No. 17/280,620, filed on 03/26/2021, which claim priority from EP18306275.1 application filed on 09/28/2018 and PCT/EP2019/076241 filed on 09/27/2019.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/22/2025 has been entered.
DETAILED ACTION
Applicant amendment and argument filed on 10/22/2025 have been received and have been carefully Considered.
Claim 6 was amended, claims 2-5 were previously cancelled, and claims 7-8 were added. Claims 1 and 6-8 are pending.
Rejection Maintained/Modified
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.
§ 103 Rejection over Legeai-Mallet in view of Jin
Claims 1 and 6-8 remain rejected under 35 U.S.C. 103 as being unpatentable over L. Legeai-Mallet et. al. (US PG Pub 2016/0051549 A1, 02/25/2016, “Legeai-Mallet” cited in the PTO-892 dated 12/03/2024) in view of M. Jin et. al. (Hum Mol Genet. 2012 Dec 15;21(26):5443-55, “Jin” cited in the PTO-892 dated 12/03/2024).
Legeai-Mallet teaches a method for treating FGFR3-related skeletal diseases comprising administering an antagonist of the FGFR3 tyrosine kinase receptor, or a composition comprising such an antagonist, to a subject in need thereof, [Pg. 2, [0016]], wherein the preferred FGFR3 antagonist is BGJ-398, as Legeai-Mallet explicitly teaches “advantageously the FGFR3 antagonist is BGJ-398, (Infigratinib, the claimed compound)” [Pg. 9, [0081], Table B (compound 1h) and claim 1]:
PNG
media_image1.png
314
588
media_image1.png
Greyscale
Legeai-Mallet teaches that the FGFR3-related skeletal disease which is caused by constitutively active mutant of the FGFR3 [Pg. 2, [0047]], includes but is not limited to thanatophoric dysplasia type I, thanatophoric dysplasia type II, hypochondroplasia, achondroplasia and SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) [Pg. 3, [0050]].
Legeai-Mallet teaches a method of using Infigratinib, BGJ-398 for treating FGFR3-related skeletal diseases, and provides in vivo experiments wherein BGJ-398 administered to dwarfism phenotype of Fgfr3Y367C/+ mice. [Pg. 16, [0147]]. Legeai-Mallet teaches that administering Infigratinib (BGJ-398) to newborn mice restores longitudinal bone growth of Fgfr3Y367C/+ femurs, induces an increase in the size of the growth plate, induces enhanced type X collagen expression, and attenuates the dwarfism phenotype of Fgfr3Y367C/+ as shown in Figures 9-11. [Pg. 14, [0123]-[0127]].
However, Legeai-Mallet does not teach administering Infigratinib to a pregnant subject.
In the same field of endeavor of treating FGFR3-related skeletal disease by administering FGFR3 inhibitors, Jin teaches treatment of FGFR3-related skeletal dysplasia syndromes including achondroplasia, hypochondroplasia and thanatophoric dysplasia (TD) using FGFR3 inhibitor peptide P3, [Jin Abstract], wherein daily peritoneal injection of the FGRF3 inhibitor is administered to pregnant Fgfr3 Neo-K644E/+ mice that had been crossed with male heterozygous EIIa-Cre mice at E16.5 until birth. [Pg. 5447, col. 1]. Jin teaches that premature closure of the spheno-occipital synchondroses in TDII mice, and the premature closure of the cranial bases of TDII mice treated with peptide P3 appeared to be normal. Jin teaches that the treatment of FGFR3-related skeletal diseases by administering FGFR3 inhibitor, P3 to pregnant mice reversed the abnormal ossification of sternebrae and the widening of the sternum and costal cartilage in TDII mice and alleviated the shortening of long bones in TDII mice, as shown in Figure 5. [Pg. 5447, col. 2, 1st para].
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of instantly claimed invention to administer FGFR3 inhibitor, Infigratinib taught by Legeai-Mallet to a pregnant subject for treating FGFR3-related skeletal disease in view of the teachings of Jin. One of ordinary skill in the art would have been motivated to treat FGFR3-related skeletal diseases by administering Infigratinib to the pregnant subject with a reasonable expectation of success, because Legeai-Mallet teaches the effectiveness of Infigratinib in treating FGFR3-related skeletal diseases, and that Infigratinib restores longitudinal bone growth of Fgfr3Y367C/+ femurs and attenuates the dwarfism pheno-type of Fgfr3Y367C/+ mice, and because Legeai-Mallet teaches administering to a subject in need thereof and Jin teaches treatment of FGFR3-related skeletal disease by administering FGFR3 inhibitors to a pregnant subject to provide treatment to the fetus with a FGFR3-related skeletal disease, as Jin teaches that the treatment of FGFR3-related skeletal diseases by administering FGFR3 inhibitor, P3 to pregnant mice reversed the abnormal ossification of sternebrae and widening of the sternum and costal cartilage and alleviated the shortening of long bones in TDII mice, and therefore, one of ordinary skill in the art would have been motivated to administer other effective FGFR3 inhibitor i.e., Infigratinib to pregnant subject for treating FGFR3-related skeletal diseases. Case law has established that it is prima facie obvious to substitute one known element for another to obtain predictable results. KSR Int'I Co. v. Teleflex, Inc., 550 U.S. 398 (2007). Therefore, the combination of Legeai-Mallet and Jin teach each and every limitation of claim 1.
With regard to claims 6 and 7, Legeai-Mallet teaches that the composition FGFR3 antagonist is administered orally or by parenteral route, including for instance intramuscular, subcutaneous, intravenous, intraperitoneal. [Pg. 13, [0098]]. Legeai-Mallet also teaches that Infigratinib is administered subcutaneously. [Pg. 16, [0147]].
Claim 8 is met for the following reasons: the combination of Legeai-Mallet and Jin teaches a method of treating achondroplasia in a fetus comprising administering to the pregnant subject an effective amount of Infigratinib. The combination of Legeai-Mallet and Jin is silent on that the claimed method increases the fetus limb length but otherwise teaches a substantially identical method as claimed. As such, it is reasonable to presume that the resulting increase in limb is inherent to the method taught by the prior art. The burden is on Applicant(s) to show that this property is different from those taught by the prior art and to establish patentable differences. See MPEP 2112.
Response to Arguments
Applicant argues:
Nothing in Jin would have led the skilled in the art to consider that P3 prevent binding of ATP to the ATP binding site of FGFR3. The two molecules (P3 of Jin and Infigratinib of Legeai-Mallet) are fundamentally thus widely different in structure (peptide/ small molecule), and site of action (extracellular for P3 vs. intracellular for Infigratinib), and most likely mode of action. Thus, one of ordinary skill in the art would have found no motivation to substitute this particular small molecule with the peptide P3. [Remarks, pages 1-2]. “The ability of a peptide to cross the placenta and reach the fetus, as demonstrated by Jin, is not predictive of the behavior of a structurally and mechanistically distinct small molecule. The pharmacokinetics, biodistribution, and placental transport properties of peptides and small molecules are not interchangeable or predictable from one another.” [Remarks, page 2, 5th para.].
Examiner response:
The majority of Applicant arguments are directed to the differences between Jin’s P3 and Infigratinib with respect to structure difference and binding site. This argument is fully considered but found not persuasive for the following reasons. As provided in MPEP 2143.02, obviousness does not require absolute predictability, but a reasonable expectation of success. One of ordinary skill in the art would have reasonable expectation of success to administer an FGFR3 inhibitor to a pregnant subject because Jin introduces administration to pregnant subject using FGFR3 inhibitor for treating exact same skeletal disease as claimed. Administration of FGFR3 inhibitor to a pregnant subject required that the FGFR3 inhibitor cross the placenta to treat the fetus. Thus, despite the fact the Jin P3 is binding the extracellular site, Jin was brought in to provide motivation to the ordinary skilled artisan to treat the fetus through the placenta by administering Infigratinib to the pregnant subject. One would presume that if an FGFR3 inhibitor crosses the placenta to treat the fetus, other FGFR3 can also cross the placenta to treat the fetus. Jin does not teach that crossing the placenta is a property of P3. Jin’s P3 and Legeai-Mallet Infigratinib are FGFR3 inhibitors, are used for treating same FGFR3 related disease, and therefore, one would be motivated by Jin to administer the potent FGFR3 inhibitor to pregnant subject. Note that the claimed FGFR3 inhibitor Infigratinib is taught by the primary reference for treating the exact same condition. Therefore, one of ordinary skill in the art would have the motivation to try Jin method of administration to obtain predictable results.
With regard to Applicant’s argument that at the time of the invention, Infigratinib was known as a possible anti-carcinoma treatment, Legeai-Mallet explicitly teaches a method for treating FGFR3-related skeletal diseases comprising administering Infigratinib, an antagonist of the FGFR3. Legeai-Mallet is directed to treating FGFR3 related skeletal disease. Thus, Infigratinib may possess activity in treating cancer, however, Legeai-Mallet used Infigratinib for treating FGFR3 skeletal disease.
Applicant argues:
The rationale offered in the office action for combining Jin and Legeai-Mallet is based on hindsight, as neither reference provides any data or scientific reasoning to support the substitution of a peptide with a small-molecule kinase inhibitor for the specific purpose of fetal therapy via maternal administration. On the contrary, the present application is the first to demonstrate, in the example, that administration of (BGJ-39) Infigratinib to pregnant mice results in fetal exposure and a measurable therapeutic effect (improved long-bone length). [Remarks, page 3, last para.].
Examiner response:
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Legeai-Mallet teaches the effectiveness of Infigratinib, an FGFR3 inhibitor, in treating FGFR3-related skeletal diseases. Jin teaches that treating fetus with an FGFR3 related skeletal disease by administering an FGFR3 inhibitor to pregnant subject reversed the abnormal ossification of sternebrae and widening of the sternum and costal cartilage and alleviated the shortening of long bones in TDII mice. Therefore, one of ordinary skill in the art would have been motivated to treat FGFR3-related skeletal diseases by administering Infigratinib to the pregnant subject with a reasonable expectation of success. Case law has established that it is prima facie obvious to substitute one known element for another to obtain predictable results. KSR Int'I Co. v. Teleflex, Inc., 550 U.S. 398 (2007).
§ 103 Rejection over Legeai-Mallet in view of Matsushita
Claims 1 and 6-8 remain rejected under 35 U.S.C. 103 as being unpatentable over L. Legeai-Mallet et. al. (US PG Pub 2016/0051549 A1, 02/25/2016, “Legeai-Mallet” cited in the PTO-892 dated 12/03/2024) in view of Matsushita et. al. (J. Neurosurg. Pediatr. 2017 Jan; 19(1):91-95, “Matsushita” cited in the PTO-892 dated 12/03/2024).
Legeai-Mallet teaches a method for treating FGFR3-related skeletal diseases comprising administering an antagonist of the FGFR3 tyrosine kinase receptor, or a composition comprising such an antagonist, to a subject in need thereof, [Pg. 2, [0016]], wherein the preferred FGFR3 antagonist is BGJ-398, as Legeai-Mallet explicitly teaches “advantageously the FGFR3 antagonist is BGJ-398, (Infigratinib, the claimed compound)” [Pg. 9, [0081], Table B (compound 1h) and claim 1]:
PNG
media_image2.png
281
527
media_image2.png
Greyscale
Legeai-Mallet teaches that the FGFR3-related skeletal disease which is caused by constitutively active mutant of the FGFR3 [Pg. 2, [0047]], includes but is not limited to thanatophoric dysplasia type I, thanatophoric dysplasia type II, hypochondroplasia, achondroplasia and SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) [Pg. 3, [0050]].
Legeai-Mallet teaches a method of using Infigratinib, BGJ-398 for treating FGFR3-related skeletal diseases, and provides in vivo experiments wherein BGJ-398 administered to dwarfism phenotype of Fgfr3Y367C/+ mice. [Pg. 16, [0147]]. Legeai-Mallet teaches that administering Infigratinib (BGJ-398) to newborn mice restores longitudinal bone growth of Fgfr3Y367C/+ femurs, induces an increase in the size of the growth plate, induces enhanced type X collagen expression, and attenuates the dwarfism phenotype of Fgfr3Y367C/+ as shown in Figures 9-11. [Pg. 14, [0123]-[0127]].
However, Legeai-Mallet does not teach administering Infigratinib to a pregnant subject.
In the same field of endeavor of treating FGFR3-related skeletal disease by administering FGFR3 inhibitors, Matsushita teaches a method of treating FGFR3 related Foramen magnum stenosis, one of the serious neurological complications in achondroplasia comprising administering a FGFR3 inhibitor, Meclozine, wherein Meclozine was administered to the pregnant mice carrying Fgfr3ach offspring from embryonic Day (ED) 14.5 to postnatal Day (PD) 4.5. Spheno-occipital and anterior intraoccipital synchondroses were histologically examined, and the bony bridges were scored on PD 4.5 and tissue concentrations of Meclozine in ED 17.5 fetuses and PD 6.5 pups were investigated. Matsushita teaches that the area of the foramen magnum was significantly smaller in 17-day-old Fgfr3ach mice and average bony bridge score is decreases in Meclozine-treated Fgfr3ach mice, however, the scores were not statistically significant between mice with and those without Meclozine treatment. [Matsushita, Abstract]. Matsushita teaches that the limited effects of prenatal treatment of Meclozine on suppression of FGFR3 signaling may be due to its relatively low placental transmission or reduction in pharmaceutical activity of Meclozine within foods, and a higher dose of Meclozine during the prenatal period would be necessary for the treatment of FMS in achondroplasia and Further studies are needed to investigate the optimal dose of Meclozine for the treatment of FMS in achondroplasia. [Pg. 94, col. 2 last para. – Pg. 95, Col. 1, 2nd].
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of instantly claimed invention to administer FGFR3 inhibitor, Infigratinib taught by Legeai-Mallet to a pregnant subject for treating FGFR3-related skeletal disease in view of the teachings of Matsushita. One of ordinary skill in the art would have been motivated to treat FGFR3-related skeletal diseases by administering Infigratinib to the pregnant subject with a reasonable expectation of success, because Legeai-Mallet teaches the effectiveness of Infigratinib in treating FGFR3-related skeletal diseases, and that Infigratinib restores longitudinal bone growth of Fgfr3Y367C/+ femurs and attenuates the dwarfism pheno-type of Fgfr3Y367C/+ mice, and because Legeai-Mallet teaches administering to a subject in need thereof, and Matsushita teaches treatment of FGFR3-related skeletal disease by administering FGFR3 inhibitors to a pregnant subject to provide treatment to the fetus with a FGFR3-related skeletal disease, as Matsushita teaches that treatment of FGFR3-related skeletal diseases by administering FGFR3 inhibitor, Meclozine to pregnant subject results in significantly smaller area of the foramen magnum and decreases in bony bridge score, and therefore, one of ordinary skill in the art would have been motivated to administer other effective FGFR3 inhibitor i.e., Infigratinib to pregnant subject for treating FGFR3-related skeletal diseases. Case law has established that it is prima facie obvious to substitute one known element for another to obtain predictable results. KSR Int'I Co. v. Teleflex, Inc., 550 U.S. 398 (2007). Therefore, the combination of Legeai-Mallet and Matsushita teach each and every limitation of claim 1.
With regard to claims 6 and 7, Legeai-Mallet teaches that the composition FGFR3 antagonist is administered orally or by parenteral route, including for instance intramuscular, subcutaneous, intravenous, intraperitoneal. [Pg. 13, [0098]]. Legeai-Mallet also teaches that Infigratinib is administered subcutaneously. [Pg. 16, [0147]].
Claim 8 is met for the following reasons: the combination of Legeai-Mallet and Matsushita teaches a method of treating achondroplasia in a fetus comprising administering to the pregnant subject an effective amount of Infigratinib. The combination of Legeai-Mallet and Matsushita is silent on that the claimed method increases the fetus limb length but otherwise teaches a substantially identical method as claimed. As such, it is reasonable to presume that the resulting increase in limb is inherent to the method taught by the prior art. The burden is on Applicant(s) to show that this property is different from those taught by the prior art and to establish patentable differences. See MPEP 2112.
Response to Arguments
Applicant argues:
Matsushita concludes that the limited effect of prenatal meclozine treatment is "probably due to low placental transmission of the drug." This finding is highly relevant because meclozine, like Infigratinib, is a small molecule. The demonstrated low placental transfer of meclozine in this context further undermines any reasonable expectation that a small-molecule kinase inhibitor such as Infigratinib would achieve effective fetal exposure when administered to the pregnant subject. [Remarks, page 2, 2nd and 3rd para. and page 4].
Examiner response:
The Applicant’s arguments have been fully considered but found not persuasive. Matsushita teaches that limited effects of prenatal treatment of meclozine on suppression of FGFR3 signaling may be due to its relatively low placental transmission and a higher dose of meclozine during the prenatal period would be necessary for the treatment of FMS in ACH. Matsushita teaches that there are several limitations in the current study including the method of administration and the reduction of the pharmaceutical activity of meclozine within foods, and further studies are needed to investigate the optimal dose of meclozine for the treatment of FMS in ACH. [Matsushita, pg. 95, col. 1, 1st para]. These Matsushita teachings does not discount the fact that it is conceivable that CMS in ACH is treatable with an FGFR3 antagonist generally. Maternal administration showing less effect on treating FGFR3-related skeletal disease does not indicate that maternal administration is not working. Obviousness requires a reasonable expectation of success and not an absolute expectation of success. The primary reference, Legeai-Mallet teaches the effectiveness of Infigratinib in treating FGFR3-related skeletal diseases, and that Infigratinib restores longitudinal bone growth of Fgfr3Y367C/+ femurs and attenuates the dwarfism pheno-type of Fgfr3Y367C/+ mice, and because Legeai-Mallet teaches administering to a subject in need thereof, and Matsushita teaches treatment of FGFR3-related skeletal disease by administering FGFR3 inhibitors to a pregnant subject to provide treatment to the fetus with a FGFR3-related skeletal disease, as Matsushita teaches that treatment of FGFR3-related skeletal diseases by administering FGFR3 inhibitor, Meclozine to a pregnant subject results in significantly smaller area of the foramen magnum and decreases in bony bridge score, and therefore, one of ordinary skill in the art would have been motivated to administer other effective FGFR3 inhibitor i.e., Infigratinib to a pregnant subject for treating FGFR3-related skeletal diseases.
Applicant argues:
“Meclozine’s established safety profile and OTC status make it a logical, low-risk candidate for in utero experiments. In contrast, Infigratinib is a targeted FGFR inhibitor developed for oncology indications, with no precedent for use in pregnancy and a fundamentally different risk/benefit and
pharmacokinetic profile.” “meclozine’s OTC status and history of use in pregnancy make it a logical, low-risk candidate for maternal dosing studies. In contrast, Infigratinib is a potent, selective FGFR inhibitor developed for cancer therapy, with no precedent for use in pregnancy and a very different safety and pharmacokinetic profile. The leap from a safe, well-tolerated OTC antihistamine to a novel anticancer agent for in utero therapy 1s not supported by the art.” [Remarks, page 4, 3rd para., and page 5, 2nd para.].
Examiner response:
This argument is fully considered but found not persuasive because there is no evidence in the record that Infigratinib is not safe to administer to pregnant subject. The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Matsushita administered an FGFR3 inhibitor to pregnant subject to treat fetus with FGFR3-related skeletal disease. One of ordinary skill would have been motivated by Matsushita to also administer other FGFR3 inhibitor to pregnant subject for treating the exact same disease. Moreover, Legeai-Mallet teaches administering to a subject in need thereof, Note that Infigratinib is presented by Legeai-Mallet as FGFR3 inhibitor for treating FGFR3-related skeletal disease not for treating cancer. Legeai-Mallet document does not include method of treating cancer, nevertheless, Legeai-Mallet is directed to treating skeletal diseases.
Applicant argues:
Applicant’s specification presents the first data showing that Infigratinib does reach the fetus and lengthens long bones—an unexpected result contradicted by Matsushita’s placental-barrier conclusion. This objective evidence rebuts any prima facie case (AEPEP § 2145). “The data indicated that BGJ398 treatment during 5 days in pregnant mice successfully repressed skeletal anomalies that occurred during embryonic stages. The treatment of the pregnant mice has permitted to cure earlier the skeletal pathology. The results suggest that BGJ398 cross the placenta at therapeutic level.” (last paragraph of page 7 of the application).
Examiner response:
Applicant is attempting to show unexpected results. As provided in MPEP 716 (b), the evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). "[A]ppellants have the burden of explaining the data in any declaration they proffer as evidence of non-obviousness." Ex parte Ishizaka, 24 USPQ2d 1621, 1624 (Bd. Pat. App. & Inter. 1992). Legeai-Mallet teaches the effectiveness of the claimed compound in treating FGFR3-skeletal disease:
100 nM of BGJ-398 for 6 days is sufficient for correcting the difference in length and normalized the size of the epiphyses. A gain of 71.86% is observed in treated Fgfr3Y357C* femurs (FIG. 9; mutant femurs cultured without BGJ-398 had a reduced longitudinal growth compared to WT femurs (Fgfr3+/+). Histological examinations using HES staining (FIG. 10A) and type X collagen labeling (FIG. 10B) were also carried out. HES staining of WT)(Fgfr3+/+) and Fgfr3Y367C/+ mice showed that growth plate from Fgfr3Y367C/+ mice have smaller mutant chondrocytes, whereas cells are larger and more spherical when femurs are cultured in the presence of 10−6 M of BGJ-398 (FIG. 10A). FIG. 10B shows that BGJ-398 induces enhanced type X collagen expression in Fgfr3Y367C/+ growth plate and that the size of the hypertrophic zone of the femur explants of Fgfr3Y367C/+ mice increases. Taken together, these results showed histological changes (increased chondrocyte proliferation and differentiation) when femurs from Fgfr3Y337/+ mice are cultivated in the presence of BGJ-398. [0160]-[0166].
The effectiveness of the FGFR3 inhibitors in treating FGFR3-related skeletal disease in a fetus by administration to pregnant subject is taught by Jin and Matsushita. Jin teaches that the treatment of FGFR3-related skeletal diseases by administering FGFR3 inhibitor, P3 to pregnant mice reversed the abnormal ossification of sternebrae and the widening of the sternum and costal cartilage in TDII mice and alleviated the shortening of long bones in TDII mice, as shown in Figure 5. [Pg. 5447, col. 2, 1st para]. Matsushita teaches that the area of the foramen magnum was significantly smaller in 17-day-old Fgfr3ach mice and average bony bridge score is decreases in Meclozine-treated Fgfr3ach mice. Thus, the teachings of Jin and Matsushita indicate the ability of FGFR3 inhibitor to cross the placenta at therapeutic level. The teachings of Legeai-Mallet showed that Infigratinib is potent in treating FGFR3-related disease. Therefore, the asserted unexpected results are insufficient and expected in view of Jin and Matsushita.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Double Patenting over USPN 9,931,341 B2 in view of Jin
Claims 1 and 8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 9,931,341 B2 cited in the PTO-892 dated 12/03/2024) in view of M. Jin et. al. (Hum Mol Genet. 2012 Dec 15;21(26):5443-55, “Jin” cited in the PTO-892 dated 12/03/2024). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claim 1 recites “a method of treating a FGFR3-related skeletal disease in a fetus comprising administering to the pregnant subject an effective amount of Infigratinib, wherein the FGFR3-related skeletal disease is achondroplasia.
U.S. Patent No. 9,931,341 B2 recites in claim 1 “a method for treating a FGFR3-related skeletal disease which comprises the step of administering a therapeutically effective amount of at least one antagonist of the FGFR3 tyrosine kinase receptor of formula:
PNG
media_image2.png
281
527
media_image2.png
Greyscale
or a composition comprising such an antagonist, to a subject in need thereof, and treating the FGFR3-related skeletal disease in said subject, wherein the FGFR3-related skeletal disease is achondroplasia.
As such, U.S. Patent No. 9,931,341 B2 teaches using FGFR3 inhibitor, Infigratinib for treating FGFR3-related skeletal disease as claimed, however, U.S. Patent No. 9,931,341 B2 does not teach administering Infigratinib to a pregnant subject to treat a fetus with FGFR3-related skeletal disease.
However, in the same field of endeavor, Jin teaches administering FGFR3 inhibitors to pregnant subject to treat FGFR3-related skeletal diseases. Jin teaches as discussed above.
The obviousness rationale is the same as discussed in the above 103 rejection (page 5), wherein this rationale is incorporated herein by reference.
Claim 8 is met by U.S. Patent No. 9,931,341 B2 and Jin over the same rationale as discussed in the above 103 rejection (page 6), wherein this rationale is incorporated herein by reference.
Double Patenting over U.S. Patent No. 9,931,341 B2 in view of Jin in further view of L. Legeai-Mallet
Claims 6 and 7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 9,931,341 B2 cited in the PTO-892 dated 12/03/2024) in view of M. Jin et. al. (Hum Mol Genet. 2012 Dec 15;21(26):5443-55, “Jin” cited in the PTO-892) as applied to claims 1 and 8 above further in view of L. Legeai-Mallet (US PG Pub 2015/0011560 A1, 01/08/2015, “L. Legeai-Mallet” cited in the PTO-892 dated 12/03/2024). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claims 6 and 7 recite “wherein Infigratinib is orally or subcutaneously administered to the pregnant subject.”
As discussed above, U.S. Patent No. 9,931,341 B2 and Jin teach a method of treating a FGFR3-related skeletal disease in a fetus comprising administering to the pregnant subject an effective amount of Infigratinib, wherein the FGFR3-related skeletal disease is chondrodysplasia and wherein chondrodysplasia is achondroplasia.
However, U.S. Patent No. 9,931,341 B2 and Jin do not teach that Infigratinib is orally or subcutaneously administered to the pregnant subject.
L. Legeai-Mallet teaches a method for treating or preventing FGFR3-related skeletal diseases which comprises the step of administering at least one antagonist of the FGFR3 tyrosine kinase receptor, or a composition comprising such an antagonist, to a subject in need thereof. [Pg. 2, 0016], wherein FGFR3 antagonist is Infigratinib. [Pg. 9, 0081], and wherein Infigratinib is administered orally, subcutaneously or intravenously, [Pg. 13, 0098]:
PNG
media_image2.png
281
527
media_image2.png
Greyscale
[Pg. 11, Table B, Claim 1].
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of instantly claimed invention to use the method taught by U.S. Patent No. 9,931,341 B2 and Jin, and administer Infigratinib to pregnant subject orally or subcutaneously in view of the teachings of L. Legeai-Mallet. One of ordinary skill in the art would have been motivated to administered Infigratinib orally or subcutaneously because L. Legeai-Mallet teaches that suitable routes for Infigratinib administration are oral and subcutaneous administration.
Double Patenting over USPN 9,931,341 B2 in view of Matsushita
Claims 1 and 8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 9,931,341 B2cited in the PTO-892 dated 12/03/2024) in view of Matsushita et. al. (J. Neurosurg. Pediatr. 2017 Jan;19(1):91-95, “Matsushita” cited in the PTO-892 dated 12/03/2024). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claim 1 recites “a method of treating a FGFR3-related skeletal disease in a fetus comprising administering to the pregnant subject an effective amount of Infigratinib, wherein the FGFR3-related skeletal disease is achondroplasia.
U.S. Patent No. 9,931,341 B2 recites in claim 1 “a method for treating a FGFR3-related skeletal disease which comprises the step of administering a therapeutically effective amount of at least one antagonist of the FGFR3 tyrosine kinase receptor of formula:
PNG
media_image2.png
281
527
media_image2.png
Greyscale
or a composition comprising such an antagonist, to a subject in need thereof, and treating the FGFR3-related skeletal disease in said subject, wherein the FGFR3-related skeletal disease is achondroplasia.
As such, U.S. Patent No. 9,931,341 B2 teaches using FGFR3 inhibitor, Infigratinib for treating FGFR3-related skeletal disease as claimed, however, US9931341B2 does not teach administering Infigratinib to pregnant subject to treat a fetus with FGFR3-related skeletal disease.
However, in the same field of endeavor, Matsushita teaches administering FGFR3 inhibitors to pregnant subject to treat FGFR3-related skeletal diseases. Matsushita teaches as discussed above.
The obviousness rationale is the same as discussed in the above 103 rejection (page 11).
Claim 8 is met by U.S. Patent No. 9,931,341 B2 and Matsushita over the same rationale as discussed in the above 103 rejection (page 12).
Double Patenting over USPN 9,931,341 B2 in view of Matsushita in further view of L. Legeai-Mallet
Claims 6 and 7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 9,931,341 B2 cited in the PTO-892 dated 12/03/2024) in view of Matsushita et. al. (J. Neurosurg. Pediatr. 2017 Jan;19(1):91-95, “Matsushita” cited in the PTO-892) as applied to claims 1 and 8 above further in view of L. Legeai-Mallet (US PG Pub 2015/0011560 A1, 01/08/2015, “L. Legeai-Mallet” cited in the PTO-892 dated 12/03/2024). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claims 6 and 7 recite “wherein Infigratinib is orally or subcutaneously administered to the pregnant subject.”
As discussed above, U.S. Patent No. 9,931,341 B2 and Matsushita teach a method of treating a FGFR3-related skeletal disease in a fetus comprising administering to the pregnant subject an effective amount of Infigratinib, wherein the FGFR3-related skeletal disease is chondrodysplasia and wherein chondrodysplasia is achondroplasia.
U.S. Patent No. 9,931,341 B2 and Matsushita do not teach that the Infigratinib is orally or subcutaneously administered to the pregnant subject.
However, in the same field of endeavor, L. Legeai-Mallet teaches the use of Infigratinib for treating FGFR3-related diseases by administering Infigratinib orally or subcutaneously.
L. Legeai-Mallet teaches as discussed above.
The obviousness rationale is the same as discussed in the Double Patenting above (page 17).
Double Patenting over US11357778B2 in view Jin
Claims 1 and 8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,357,778 B2 cited in the PTO-892 dated 12/03/2024) in view of M. Jin et. al. (Hum Mol Genet. 2012 Dec 15;21(26):5443-55, “Jin” cited in the PTO-892 dated 12/03/2024). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claim 1 recites “a method of treating a FGFR3-related skeletal disease in a fetus comprising administering to the pregnant subject an effective amount of Infigratinib, wherein the FGFR3-related skeletal disease is achondroplasia.
U.S. Patent No. 11,357,778 B2 recites is claim 1 “method for treating hypochondroplasia which comprises the step of administering a therapeutically effective amount of an antagonist of the FGFR3 tyrosine kinase receptor of formula:
PNG
media_image2.png
281
527
media_image2.png
Greyscale
or a composition comprising a therapeutically effective amount of such an antagonist, to a subject in need thereof.
As such, U.S. Patent No. 11,357,778 B2 teach using FGFR3 inhibitor, Infigratinib for treating FGFR3-related skeletal disease as claimed, however, U.S. Patent No. 11,357,778 B2 does not teach administering Infigratinib to pregnant subject to treat a fetus with FGFR3-related skeletal disease.
However, in the same field of endeavor, Jin teaches administering FGFR3 inhibitors to pregnant subject to treat FGFR3-related skeletal diseases. Jin teaches as discussed above.
The obviousness rationale is the same as discussed in the above 103 rejection (page 5).
Claim 8 is met by U.S. Patent No. 9,931,341 B2 and Jin over the same rationale as discussed in the above 103 rejection (page 6), wherein this rationale is incorporated herein by reference.
Double Patenting over USPN 11,357,778 B2 in view of Jin in further view of L. Legeai-Mallet
Claims 6 and 7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,357,778 B2 cited in the PTO-892 dated 12/03/2024) in view of M. Jin et. al. (Hum Mol Genet. 2012 Dec 15;21(26):5443-55, “Jin” cited in the PTO-892 dated 12/03/2024) as applied to claims 1 and 8 above further in view of L. Legeai-Mallet (US PG Pub 2015/0011560 A1, 01/08/2015, “L. Legeai-Mallet” cited in the PTO-892). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claim 6 recites “wherein Infigratinib is orally or subcutaneously administered to the pregnant subject.”
As discussed above, U.S. Patent No. 11,357,778 B2 and Jin teach a method of treating a FGFR3-related skeletal disease in a fetus comprising administering to the pregnant subject an effective amount of Infigratinib, wherein the FGFR3-related skeletal disease is chondrodysplasia and wherein chondrodysplasia is achondroplasia.
U.S. Patent No. 11,357,778 B2 and Jin do not teach that the Infigratinib is orally or subcutaneously administered to the pregnant subject.
However, in the same field of endeavor, L. Legeai-Mallet teaches the use of Infigratinib for treating FGFR3-related disease by administering Infigratinib orally or subcutaneously. L. Legeai-Mallet teaches as discussed above.
The obviousness rationale is the same as discussed in the above Double Patenting (page 17).
Double Patenting over USPN 11,357,778 B2 in view of Matsushita
Claims 1 and 8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,357,778 B2 cited in the PTO-892 dated 12/03/2024) in view of Matsushita et. al. (J. Neurosurg. Pediatr. 2017 Jan;19(1):91-95, “Matsushita” cited in the PTO-892 dated 12/03/2024). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claim 1 recites “a method of treating a FGFR3-related skeletal disease in a fetus comprising administering to the pregnant subject an effective amount of Infigratinib, wherein the FGFR3-related skeletal disease is achondroplasia.
U.S. Patent No. 11,357,778 B2 recites in claim 1 “method for treating hypochondroplasia which comprises the step of administering a therapeutically effective amount of an antagonist of the FGFR3 tyrosine kinase receptor of formula:
PNG
media_image2.png
281
527
media_image2.png
Greyscale
or a composition comprising a therapeutically effective amount of such an antagonist, to a subject in need thereof.
As such, U.S. Patent No. 11,357,778 B2 teaches using FGFR3 inhibitor, Infigratinib for treating FGFR3-related skeletal disease as claimed, however, U.S. Patent No. 11,357,778 B2 does not teach administering Infigratinib to pregnant subject to treat a fetus with FGFR3-related skeletal disease.
However, in the same field of endeavor, Matsushita teaches administering FGFR3 inhibitors to pregnant subject to treat FGFR3-related skeletal diseases. Matsushita teaches as discussed above.
The obviousness rationale is the same as discussed in the above 103 rejection (page 11).
Claim 8 is met by U.S. Patent No. 9,931,341 B2 and Matsushita over the same rationale as discussed in the above 103 rejection (page 12).
Double Patenting over USPN 11,357,778 B2 in view of Matsushita in further view of L. Legeai-Mallet
Claims 6 and 7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,357,778 B2 cited in the PTO-892 dated 12/03/2024) in view of Matsushita et. al. (J. Neurosurg. Pediatr. 2017 Jan;19(1):91-95, “Matsushita” cited in the PTO-892 dated 12/03/2024) as applied to claims 1 and 8 above further in view of L. Legeai-Mallet (US PG Pub 2015/0011560 A1, 01/08/2015, “L. Legeai-Mallet” cited in the PTO-892 dated 12/03/2024). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claims 6 and 7 recite “wherein Infigratinib is orally or subcutaneously administered to the pregnant subject.”
As discussed above, U.S. Patent No. 11,357,778 B2 and Matsushita teach a method of treating a FGFR3-related skeletal disease in a fetus comprising administering to the pregnant subject an effective amount of Infigratinib, wherein the FGFR3-related skeletal disease is achondroplasia.
U.S. Patent No. 11,357,778 B2 and Matsushita do not teach that Infigratinib is orally or subcutaneously administered to the pregnant subject.
However, in the same field of endeavor, L. Legeai-Mallet teaches the use of Infigratinib for treating FGFR3-related diseases by administering Infigratinib orally or subcutaneously.
L. Legeai-Mallet teaches as discussed above.
The obviousness rationale is the same as discussed in the above Double Patenting (page 17).
Response to Arguments
Applicant’s arguments against Double Patenting Rejections are parallel to the argument of the 103 Rejection above. The Office’s rebuttal of these arguments is incorporated herein by reference. See Response to Argument above.
Double Patenting over copending application No. 18/717,727 in view Jin
Claims 1 and 8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6 and 8 of copending application No. 18/717,727 (reference application) in view of M. Jin et. al. (Hum Mol Genet. 2012 Dec 15;21(26):5443-55, “Jin” cited in the PTO-892 dated 12/03/2024). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claim 1 recites “a method of treating a FGFR3-related skeletal disease in a fetus comprising administering to the pregnant subject an effective amount of Infigratinib, wherein the FGFR3-related skeletal disease is achondroplasia.
copending application No. 18/717,727 recites “a method of FGFR-related bone repair and treating FGFR-related bone formation impairment in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one FGFR3 tyrosine kinase inhibitor, wherein the at least one FGFR3 tyrosine kinase inhibitor is BGJ398, wherein FGFR3-related skeletal disease is achondroplasia.
As such, copending application No. 18/717,727 teach using FGFR3 inhibitor, Infigratinib for treating FGFR3-related skeletal disease as claimed, however, copending application No. 18/717,727 does not teach administering Infigratinib to pregnant subject to treat a fetus with FGFR3-related skeletal disease.
However, in the same field of endeavor, Jin teaches administering FGFR3 inhibitors to pregnant subject to treat FGFR3-related skeletal diseases. Jin teaches as discussed above.
The obviousness rationale is the same as discussed in the above 103 rejection (page 5).
Claim 8 is met by copending application No. 18/717,727 and Jin over the same rationale as discussed in the above 103 rejection (page 6), wherein this rationale is incorporated herein by reference.
Double Patenting over copending application No. 18/717,727 in view of Jin in further view of L. Legeai-Mallet
Claims 6 and 7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6 and 8 of copending application No. 18/717,727 (reference application) in view of M. Jin et. al. (Hum Mol Genet. 2012 Dec 15;21(26):5443-55, “Jin” cited in the PTO-892 dated 12/03/2024) as applied to claims 1 and 8 above further in view of L. Legeai-Mallet (US PG Pub 2015/0011560 A1, 01/08/2015, “L. Legeai-Mallet” cited in the PTO-892). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claims 6 and 7 recites “wherein Infigratinib is orally or subcutaneously administered to the pregnant subject.”
As discussed above, copending application No. 18/717,727 and Jin teach a method of treating a FGFR3-related skeletal disease in a fetus comprising administering to the pregnant subject an effective amount of Infigratinib, wherein the FGFR3-related skeletal disease is chondrodysplasia and wherein chondrodysplasia is achondroplasia.
copending application No. 18/717,727 and Jin do not teach that the Infigratinib is orally or subcutaneously administered to the pregnant subject.
However, in the same field of endeavor, L. Legeai-Mallet teaches the use of Infigratinib for treating FGFR3-related disease by administering Infigratinib orally or subcutaneously. L. Legeai-Mallet teaches as discussed above.
The obviousness rationale is the same as discussed in the above Double Patenting (page 17).
Double Patenting over copending application No. 18/717,727 in view of Matsushita
Claims 1 and 8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6 and 8 of copending application No. 18/717,727 (reference application) in view of Matsushita et. al. (J. Neurosurg. Pediatr. 2017 Jan;19(1):91-95, “Matsushita” cited in the PTO-892 dated 12/03/2024). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claim 1 recites “a method of treating a FGFR3-related s