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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 03/12/2026 has been entered.
Priority
This application is a 371 of PCT/US20/48704 filed 08/31/2020 which claims benefit of provisional application 62/893,535 filed 08/29/2019. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Status of the Claims
Claim 2 is amended. Claim 3 is cancelled.
Claims 2, 7, 10-19 and 21-24 are pending (claim set filed 03/12/2026) and are examined on the merits herein.
Withdrawal of Rejections
The response and amendment filed on 03/12/2026 are acknowledged. All of the amendment and arguments have been thoroughly reviewed and considered.
For the purposes of clarity of the record, the reasons for the Examiner's withdrawal and/or maintaining if applicable, of the substantive or essential claim rejections are detailed directly below and/or in the Examiner's response to arguments section.
The previous claim 3 35 U.S.C. 112(d) rejection has been withdrawn necessitated by cancellation of claim 3.
The previous claims 2, 3, 7, 10-16, 19 and 21-24 35 U.S.C. 102(a)(1) rejection has been withdrawn necessitated by amendment of claim 2, cancellation of claim 3 and Applicant’s arguments which are persuasive.
Claim Objections
Claim 2 is objected to because of the following informalities:
Claim 2 recites: “in a subject less than 3 years old and has a total score”. Applicant is suggested to replace recitation with: “in a subject less than 3 years old and having a total score”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 19 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 19 recites limitations i) and ii) connected with and/or. The limitation i), i.e. “the subject has a total score on the motor and language subscales of about 3 to about 6 points” is claimed in claim 2 from which claim 19 depends. When limitations i) and ii) are connected with ‘or’, claim 19 does not further limit claim 2.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
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.
Claims 2, 7, 10-16, 19 and 21-24 are rejected under 35 U.S.C. 103 as being unpatentable over European Medicine Agency (EMA) (European Medicine Agency, Brineura: ANNEX I Summary of Product Characteristics, 2017, [retrieved on 09/20/2024]. Retrieved from the Internet:
<http://ec.europa.eu/health/documents/communityregister/2017/20170530137963/anx_137963_en.p
df> on record in IDS).
Regarding claim 2, EMA teaches medicinal product Brineura, containing cerliponase alfa, for treatment of neuronal ceroid lipofuscinosis type 2 (CLN2) disease which is tripeptidyl peptidase 1 (TPP1) deficiency (p. 2, Therapeutic indications). Cerliponase alfa is a recombinant form of human TPP1 (rhTPP1) (p. 9, Mechanism of action). EMA describes administration of cerliponase alpha by intracerebroventricular infusion (p. 2, Posology). EMA teaches treatment with 300 mg cerliponase alfa (rhTPP1) once every other week (p. 2, Posology). EMA discloses evaluation of the disease progression by clinical rating scale for motor and language (ML) functions encompassing scores of 3 (grossly normal) to 0 (profoundly impaired) (p. 10, 1st paragraph, Table 3). EMA discloses that the mean total score for the patients in clinical studies was 3.5 (p. 10, 2nd paragraph). EMA discloses results of two clinical studies on CLN2 patients, aged 3 to 8 years, including treatment with 300 mg Brineura (p. 9-11, Clinical efficacy and safety). EMA shows that treatment resulted in the significant delay of the decline in motor and language functions in comparison with untreated patients (p. 10-11, Figure 2). Even though children less than 3 years old were not included in the pivotal study, EMA mentions that it is important to initiate treatment in children as young as possible (p. 12, Paediatric population). Additionally, EMA provides recommended doses for patients less than 3 years old as shown in Table 1 (p. 3). It is noted that less than 3 years old could be even 2 years and 11 months which is close to 3 years old.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that treatment of a subject less than 3 years old with ML score of 3-6 by method taught by EMA can delay the onset of CLN2 disease or a symptom. One would be motivated to expect that since EMA teaches the same method steps, the same formulation, routes of administration, dosage and regimen, the same ML score in the population and points to necessity of initiating treatment as early as possible and provides instructions on the dosage of patients less than 3 years old and hence EMA treatment will necessarily delay the onset or symptoms of CLN2 disease in a subject less than 3 years old with ML score of 3-6. MPEP 2145.II states: “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention ." Thus, EMA teaching renders claim 2 obvious.
Regarding claims 7 and 10-12, EMA teaches doses for patients with age more than 1 year old and less than 2 years old as 200 mg for the first 4 doses and 300 mg for subsequent doses (p. 3, Table 1). Thus, EMA teaching renders claims 7 and 10-12 obvious.
Regarding claims 13 and 14, EMA teaches doses for patients with age more than 6 months old and less than 1 year old as 150 mg (p. 3, Table 1). Thus, EMA teaching renders claims 13 and 14 obvious.
Regarding claims 15 and 16, EMA teaches doses for patients with age less than 6 months old as 100 mg (p. 3, Table 1). Thus, EMA teaching renders claims 15 and 16 obvious.
Regarding claim 19, EMA teaches evaluation of the disease progression by clinical rating scale for motor and language functions encompassing scores of 3 (grossly normal) to 0 (profoundly impaired) (p. 10, 1st paragraph, Table 3). EMA discloses that the mean total score for the patients in clinical studies was 3.5 (p. 10, 2nd paragraph). Thus, EMA teaching renders claim 19 obvious.
Regarding claim 21, EMA recommends pre-treatment of patients with antihistamines with or without antipyretics 30 to 60 min prior to treatment with cerliponase alfa (rhTPP1) (p. 2, Posology). Thus, EMA teaching renders claim 21 obvious.
Regarding claim 22 and 23, EMA teaches excipients in Brineura formulation including instant excipients, e.g. sodium chloride, potassium chloride and water for injections (p. 22, List of excipients). Thus, EMA teaching renders claims 22 and 23 obvious.
Regarding claim 24, EMA recommends administration of the flushing solution in order to fully administer Brineura formulation (p. 4, 1st paragraph). Thus, EMA teaching renders claim 24 obvious.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over EMA (European Medicine Agency, Brineura: ANNEX I Summary of Product Characteristics, 2017, [retrieved on 09/20/2024]. Retrieved from the Internet: <http://ec.europa.eu/health/documents/communityregiste /2017/20170530137963/anx_137963_en.pdf> on record in IDS) in view of Lukacs (Lukacs et al. Chimica Clinica Acta, 2019, 492, 69-71).
The teaching of EMA has been set forth above.
EMA does not teach decrease in TPP1 enzyme activity in a subject based on blood test.
Lukacs teaches fluorometric test for TPP1 activity in blood samples to diagnose CNL2 (Title). Test performed on 50 samples from patients with CNL2 confirmed by clinical and molecular genetic data identified decline in CLN2 activity comparing to control samples (Abstract, p. 70, Figure 1). Lukacs mentions: “We consider our TPP1 test on DBS (dried blood samples) to be a reliable, convenient and inexpensive tool for a first diagnostic step in suspected CLN2 disease.” (Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to add teachings of Lukacs to EMA teaching on treatment of CLN2 patients and perform test for TPP1 activity on blood samples of patients to confirm the diagnosis. One would have been motivated to make this combination because Lukacs teaches test to be reliable and convenient for diagnosing CLN2 disease. A skilled artisan would have reasonably expected success in this combination since EMA provided formulation and method for treatment of TPP1 deficiency and Lukacs described test for confirmation of TPP1 deficiency by measuring its activity in blood samples. Thus, EMA and Lukacs teachings render claim 17 obvious.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over EMA (European Medicine Agency, Brineura: ANNEX I Summary of Product Characteristics, 2017, [retrieved on 09/20/2024]. Retrieved from the Internet: <http://ec.europa.eu/health/documents/communityregister /2017/20170530137963/anx_137963_en.pdf> on record in IDS) in view of Lester (US 20160324942 A1).
The teaching of EMA has been set forth above.
EMA does not teach the subject to be a sibling of an individual diagnosed with CLN2.
Lester teaches formulations of human recombinant TPP1 and methods of treatment of CLN2 (Abstract). Lester discloses method of treating a subject having CLN2 disease or family history of CLN2 disease (paragraph 0054). Lester describes term “family history” referring to a subject having blood relative diagnosed with CLN2, e.g. sibling (paragraph 0031). Lester mentions that CLN2 disease has predominantly late infantile phenotype with the first symptoms appearing after 3 years of age and that the patient death typically occurs between 6 and 12 years old (paragraph 0005).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to add treatment of sibling of CLN2 patient to method of treatment of CLN2 with rhTPP1 as described by EMA for patients less than 3 years old. One would have been motivated to do so because Lester teaches that the first symptoms of CLN2 appear after 3 years of age and therefore presymptomatic treatment of sibling of CLN2 patient, which can potentially have CLN2, will prevent or slow down the disease. Sibling is the most probable subject with family history of CLN2 disease because patients with CLN2 do not survive to adulthood. A skilled artisan would have reasonably expected success in this combination since both EMA and Lester teach treatment of CLN2 patients with rhTPP1. Thus, EMA and Lester teachings render claim 18 obvious.
Response to Arguments
Applicant's arguments filed 03/12/2026 have been fully considered but they are not persuasive.
Applicant argues (addressing p. 7-10 of the Remarks) that the method to delay onset of CLN2 disease or a symptom thereof in the patient population as claimed is not inherent in the EMA population. EMA describes possibility of treating CLN2 patients less than 3 years old, does not provide clinical data and does not describe that population to have the total ML score of about 3 to about 6. Applicant further argues that selection of patients with this ML score would not necessarily follow from EMA disclosure. Applicant argues that one would not expect the same outcome in older children and in infants due to differences in treatment of infants and older children. Applicant provides prior art in support of the statement that treatment and efficacy in infants and younger children is not necessarily comparable and predictable. Applicant refers to Example 10 of application describing that treatment of patients less than 3 years old with the dose less than given to older children was effective in reducing worsening of the disease symptoms. Applicant describes post-filed evidence supporting the disclosure of the specification and mentioned that these results would not necessarily follow the disclosure of EMA which provides the results of delaying the decline in symptoms of patients already suffering from CLN2 disease. These arguments are not persuasive because:
The previous rejection under 35 U.S.C. 102 was withdrawn and under further consideration the 35 U.S.C. 103 obviousness rejection was applied. Although EMA does not expressly teach treatment of patients less than 3 years old with the total ML score of 3-6 and does not provide clinical data, EMA teaches the same method steps, i.e. administering rhTPP1; the same formulation, i.e. rhTPP1; routes of administration, i.e. intracerebroventricular infusion; the same dosage and regimen, i.e. 300 mg every other week (p. 2, Posology); the same population, i.e. average total ML score of 3.5 (p. 10, 2nd paragraph) as claim 1 and EMA provides detailed instructions for the dosage for different age categories of patients less than 3 years old (p. 3). That provides motivation to expect that EMA treatment will necessarily delay the onset or symptoms of CLN2 disease in a subject less than 3 years old with ML score of 3-6. The post-filing data provided by the Applicant confirm that.
It is not surprising that the patient population of less than 3 years old had the total ML score from 3 to 6 since as described in the specification, children with CLN2 disease typically develop normally until about 3 years of age when first symptoms emerge (paragraph 0005). Nevertheless, EMA population has total ML score ranging from 1 to 6 indicating that not only patients suffering from the symptoms but also patients with total score 6, i.e. with normal motor and language functions, were included in the study and EMA mentions that no patients with the advanced disease progression were studied (p. 10, 2nd paragraph). The average total ML score in EMA is 3.5 which is within the instant range.
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.
First Rejection
Claims 2, 7, 10-16, 19 and 21-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2-4 and 7 of U.S. Patent No. 11229687 (Lester 1) in view of European Medicine Agency (EMA) (European Medicine Agency, Brineura: ANNEX I Summary of Product Characteristics, 2017, [retrieved on 09/20/2024]. Retrieved from the Internet: <http://ec.europa.eu/health/documents/communityregister/2017/20170530137963/anx_137963_en.p df> on record in IDS).
Claim 2 of instant application is directed to a method of delaying the onset or symptoms of CLN2 in a subject less than 3 years old and having the total ML score of 3-6 comprising administering rhTPP1 for specified routes of administration wherein the dosage of about 300 mg or less is administered every 2 weeks.
Regarding claim 2, claim 2 of Lester 1 teaches a method of preventing symptoms of CLN2 comprising administering rhTPP1 to a subject in need at a dose of 300 mg. Claim 3 of Lester 1 teaches routes of administration including instant routes in claim 2. Claim 7 of Lester 1 teaches administration every other week that corresponds to instant every 2 weeks.
Lester 1 does not teach treating subject of less than 3 years old and having the total ML score of 3-6.
EMA teaches treatment of CNL2 with Brineura, containing cerliponase alfa (p. 2, Therapeutic indications) which is a recombinant form of human TPP1 (rhTPP1) (p. 9, Mechanism of action). EMA provides instructions for treatment of patients less than 3 years old with doses of 300 mg rhTPP1 and lower as shown in Table 1 (p. 3). EMA mentions that it is important to initiate treatment in children as young as possible (p. 12, Paediatric population). EMA teaches evaluation of the disease progression by clinical rating scale for motor and language functions encompassing scores of 3 (grossly normal) to 0 (profoundly impaired) (p. 10, 1st paragraph, Table 3). EMA discloses that the mean total score for the patients in clinical studies was 3.5 (p. 10, 2nd paragraph). EMA shows that treatment resulted in the significant delay of the decline in motor and language functions in comparison with untreated patients (p. 10-11, Figure 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to add EMA teaching on treatment of patients less than 3 years old and having the total ML score of 3-6 to Lester 1 teaching on CLN2 treatment. One would have been motivated to make this modification because EMA mentions importance of initiation of CLN2 treatment for children as early as possible and provides instructions for such treatment. A skilled artisan would have reasonably expected success in this modification since both Lester 1 and EMA teach treatment of CLN2 with rhTPP1. Thus, claims 2, 3 and 7 of Lester 1 and EMA teachings render claim 2 obvious.
Instant claim 7 is directed to the subject greater or about 2 years old or greater than or about 1 year old. Instant claims 10-12 are drawn to a dosage of 200 mg rhTPP1 (claim 10), 1st-4th dosages of 200 mg and 5th and subsequent dosages greater than 200 mg (claim 11) and 5th and subsequent dosages of 300 mg rhTPP1 (claim 12).
Regarding claims 7 and 10-12, EMA teaches doses for patients with age more than 1 year old and less than 2 years old as 200 mg for the first 4 doses and 300 mg for subsequent doses (p. 3, Table 1).
Instant claim 13 is directed to the subject greater than or about 6 months old and less than 1 year old. Instant claim 14 is drawn to a dosage for the subject of claim 13 of about 150 mg rhTPP1.
Regarding claims 13 and 14, EMA teaches doses for patients with age more than 6 months old and less than 1 year old as 150 mg (p. 3, Table 1).
Instant claim 15 is directed to the subject less than or about 6 months old. Instant claim 16 is drawn to a dosage for the subject of claim 15 of about 100 mg rhTPP1.
Regarding claims 15 and 16, EMA teaches doses for patients with age less than 6 months old as 100 mg (p. 3, Table 1).
Instant claim 19 is directed to the subject having the total ML score of 3-6.
Regarding claim 19, EMA teaches evaluation of the disease progression by clinical rating scale for motor and language functions encompassing scores of 3 (grossly normal) to 0 (profoundly impaired) (p. 10, 1st paragraph, Table 3). EMA discloses that the mean total score for the patients in clinical studies was 3.5 (p. 10, 2nd paragraph).
Instant claim 21 is directed to administering to the subject antihistamine with or without antipyretics before administration of rhTPP1.
Regarding claim 21, EMA recommends pre-treatment of patients with antihistamines with or without antipyretics 30 to 60 min prior to treatment with cerliponase alfa (rhTPP1) (p. 2, Posology).
Instant claim 24 is directed to administering to the subject a flush solution after administering the formulation.
Regarding claim 24, EMA recommends administration of the flushing solution in order to fully administer Brineura formulation (p. 4, 1st paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to follow EMA instructions of the dosage for infants of various age and apply these instruction for CLN2 treatment based on Lester 1 teaching on patients less than 3 years old and having the total ML score of 3-6, administer rhTPP1 antihistamine with or without antipyretics before administration of rhTPP1 and administer the flushing solution after rhTPP1 administration. One would have been motivated to do that because EMA showed rhTPP1 treatment to significantly delay the decline in motor and language functions in comparison with untreated patients and EMA mentioned importance of initiation of CLN2 treatment for children as early as possible and provided instructions for such treatment. A skilled artisan would have reasonably expected success in this modification since both Lester 1 and EMA teach treatment of CLN2 with rhTPP1. Thus, claims 2, 3 and 7 of Lester 1 and EMA teachings render claims 7, 10-16, 19, 21 and 24 obvious.
Claim 22 of instant application is drawn to formulation comprising rhTPP1 and at least one pharmaceutically acceptable carrier, diluent or excipient. Claim 23 of instant application recites carriers, diluents and excipients. Claim 4 of Lester 1 teaches rhTPP1 composition comprising potassium chloride, magnesium chloride and calcium chloride dehydrate recited in instant claim 23. Thus, claims 2-4 and 7 of Lester 1 and EMA teachings render claims 22 and 23 obvious.
Claim 17 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2, 3 and 7 of U.S. Patent No. 11229687 (Lester 1) in view of European Medicine Agency (EMA) (European Medicine Agency, Brineura: ANNEX I Summary of Product Characteristics, 2017, [retrieved on 09/20/2024]. Retrieved from the Internet: <http://ec.europa.eu/health/documents/communityregister/2017/20170530137963/anx_137963_en.p df> on record in IDS) as applied to claim 1 above, and further in view of Lukacs (Lukacs et al. Chimica Clinica Acta, 2019, 492, 69-71).
Instant claim 17 is directed to decrease in TPP1 activity based on blood test.
Lester 1 and EMA teachings have been set forth above.
Lester 1 and EMA do not teach decrease in TPP1 enzyme activity in a subject based on blood test.
Lukacs teaches fluorometric test for TPP1 activity in blood samples to diagnose CNL2 (Title). Test performed on 50 samples from patients with CNL2 confirmed by clinical and molecular genetic data identified decline in CLN2 activity comparing to control samples (Abstract, p. 70, Figure 1). Lukacs mentions: “We consider our TPP1 test on DBS (dried blood samples) to be a reliable, convenient and inexpensive tool for a first diagnostic step in suspected CLN2 disease.” (Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to add teachings of Lukacs to method of treatment of CLN2 patients based on Lester 1 and EMA teachings and perform test for TPP1 activity on blood samples of patients to confirm the diagnosis. One would have been motivated to make this combination because Lukacs teaches test to be reliable and convenient for diagnosing CLN2 disease. A skilled artisan would have reasonably expected success in this combination since Lester 1 and EMA provided formulation and method for treatment of TPP1 deficiency and Lukacs described test for confirmation of TPP1 deficiency by measuring its activity in blood samples. Thus, reference claims 2, 3 and 7, EMA and Lukacs teaching render claim 17 obvious.
Claim 18 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2, 3 and 7 of U.S. Patent No. 11229687 (Lester 1) in view of European Medicine Agency (EMA) (European Medicine Agency, Brineura: ANNEX I Summary of Product Characteristics, 2017, [retrieved on 09/20/2024]. Retrieved from the Internet: <http://ec.europa.eu/health/documents/communityregister/2017/20170530137963/anx_137963_en.p df> on record in IDS) as applied to claim 1 above, and further in view of Lester (US 20160324942 A1).
Instant claim 18 is directed to the subject being sibling of an individual diagnosed with CLN2.
Lester 1 and EMA teachings have been set forth above.
Lester 1 and EMA does not teach the subject to be a sibling of an individual diagnosed with CLN2.
Lester teaches formulations of human recombinant TPP1 and methods of treatment of CLN2 (Abstract). Lester discloses method of treating a subject having CLN2 disease or family history of CLN2 disease (paragraph 0054). Lester describes term “family history” referring to a subject having blood relative diagnosed with CLN2, e.g. sibling (paragraph 0031). Lester mentions that CLN2 disease has predominantly late infantile phenotype with the first symptoms appearing after 3 years of age and that the patient death typically occurs between 6 and 12 years old (paragraph 0005).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to add treatment of sibling of CLN2 patient to method of treatment of CLN2 with rhTPP1 based on Lester 1 teaching and as described by EMA for patients less than 3 years old. One would have been motivated to do so because Lester teaches that the first symptoms of CLN2 appear after 3 years of age and therefore presymptomatic treatment of sibling of CLN2 patient, which can potentially have CLN2, will prevent or slow down the disease. Sibling is the most probable subject with family history of CLN2 disease because patients with CLN2 do not survive to adulthood. A skilled artisan would have reasonably expected success in this combination since Lester 1, EMA and Lester teach treatment of CLN2 patients with rhTPP1. Thus, reference claims 2, 3 and 7, EMA and Lester teachings render claim 18 obvious.
Therefore, since instant claims 2, 7, 10-19 and 21-24 encompass the subject matter of the reference claims 2-4 and 7, they are rejected under obviousness double patenting.
Second Rejection
Claims 2, 7, 10-16, 18, 19 and 21-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 7 and 9-11 of U.S. Patent No. 10758598 (Lester 2) in view of European Medicine Agency (EMA) (European Medicine Agency, Brineura: ANNEX I Summary of Product Characteristics, 2017, [retrieved on 09/20/2024]. Retrieved from the Internet: <http://ec.europa.eu/health/documents/communityregister/2017/20170530137963/anx_137963_en.p df> on record in IDS).
Claim 2 of instant application is directed to a method of delaying the onset or symptoms of CLN2 in a subject less than 3 years old and having the total ML score of 3-6 comprising administering rhTPP1 for specified routes of administration wherein the dosage of about 300 mg or less is administered every 2 weeks.
Regarding claim 2, claim 1 of Lester 2 teaches a method of preventing symptoms of CLN2 comprising administering of about 250 mg to about 350 mg of rhTPP1 to a subject in need. Thus, Lester 2 teaches treatment of CLN2 with the instant composition and dosage. Claim 9 of Lester 2 is drawn to administration once every 2 weeks. Claim 10 of Lester 2 teaches administration via instant routes.
Lester 2 does not teach treating subject of less than 3 years old and having the total ML score of 3-6.
EMA teaches treatment of CNL2 with Brineura, containing cerliponase alfa (p. 2, Therapeutic indications) which is a recombinant form of human TPP1 (rhTPP1) (p. 9, Mechanism of action). EMA provides instructions for treatment of patients less than 3 years old with doses of 300 mg rhTPP1 and lower as shown in Table 1 (p. 3). EMA mentions that it is important to initiate treatment in children as young as possible (p. 12, Paediatric population). EMA teaches evaluation of the disease progression by clinical rating scale for motor and language functions encompassing scores of 3 (grossly normal) to 0 (profoundly impaired) (p. 10, 1st paragraph, Table 3). EMA discloses that the mean total score for the patients in clinical studies was 3.5 (p. 10, 2nd paragraph). EMA shows that treatment resulted in the significant delay of the decline in motor and language functions in comparison with untreated patients (p. 10-11, Figure 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to add EMA teaching on treatment of patients less than 3 years old and having the total ML score of 3-6 to Lester 2 teaching on CLN2 treatment. One would have been motivated to make this modification because EMA mentions importance of initiation of CLN2 treatment for children as early as possible and provides instructions for such treatment. A skilled artisan would have reasonably expected success in this modification since both Lester 2 and EMA teach treatment of CLN2 with rhTPP1. Thus, claims 1, 9 and 10 of Lester 2 and EMA teachings render claim 2 obvious.
Instant claim 7 is directed to the subject greater or about 2 years old or greater than or about 1 year old. Instant claims 10-12 are drawn to a dosage of 200 mg rhTPP1 (claim 10), 1st-4th dosages of 200 mg and 5th and subsequent dosages greater than 200 mg (claim 11) and 5th and subsequent dosages of 300 mg rhTPP1 (claim 12).
Regarding claims 7 and 10-12, EMA teaches doses for patients with age more than 1 year old and less than 2 years old as 200 mg for the first 4 doses and 300 mg for subsequent doses (p. 3, Table 1).
Instant claim 13 is directed to the subject greater than or about 6 months old and less than 1 year old. Instant claim 14 is drawn to a dosage for the subject of claim 13 of about 150 mg rhTPP1.
Regarding claims 13 and 14, EMA teaches doses for patients with age more than 6 months old and less than 1 year old as 150 mg (p. 3, Table 1).
Instant claim 15 is directed to the subject less than or about 6 months old. Instant claim 16 is drawn to a dosage for the subject of claim 15 of about 100 mg rhTPP1.
Regarding claims 15 and 16, EMA teaches doses for patients with age less than 6 months old as 100 mg (p. 3, Table 1).
Instant claim 19 is directed to the subject having the total ML score of 3-6.
Regarding claim 19, EMA teaches evaluation of the disease progression by clinical rating scale for motor and language functions encompassing scores of 3 (grossly normal) to 0 (profoundly impaired) (p. 10, 1st paragraph, Table 3). EMA discloses that the mean score for the patients in clinical studies was 3.5 (p. 10, 2nd paragraph).
Instant claim 21 is directed to administering to the subject antihistamine with or without antipyretics before administration of rhTPP1.
Regarding claim 21, EMA recommends pre-treatment of patients with antihistamines with or without antipyretics 30 to 60 min prior to treatment with cerliponase alfa (rhTPP1) (p. 2, Posology).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to follow EMA instructions of the dosage for infants of various age and apply these instruction for CLN2 treatment based on Lester 2 teaching of patients less than 3 years old and having the total ML score of 3-6, administer rhTPP1 antihistamine with or without antipyretics before administration of rhTPP1 and administration the flushing solution after rhTPP1 administration. One would have been motivated to do that because EMA showed rhTPP1 treatment to significantly delay the decline in motor and language functions in comparison with untreated patients and EMA mentioned importance of initiation of CLN2 treatment for children as early as possible and provided instructions for such treatment. A skilled artisan would have reasonably expected success in this modification since both Lester 2 and EMA teach treatment of CLN2 with rhTPP1. Thus, claims 1, 9 and 10 of Lester 2 and EMA teachings render claims 7, 10-16, 19 and 21 obvious.
Claim 18 of instant application is drawn to the subject being a sibling of individual diagnosed with CLN2. Claim 7 of Lester 2 teaches the subject with the family history of CLN2 disease. It would have been obvious to one of ordinary skill in the art to add treatment of sibling of CLN2 patient to method of treatment of CLN2 with rhTPP1 based on Lester 2 teaching. One would have been motivated to do that because the closest relative to patient with CLN2 disease will be sibling since CLN2 is an infantile genetic disease and since patients with CLN2 do not survive to adulthood, presymptomatic treatment of sibling of CLN2 patient, which can potentially have CLN2, will prevent or slow down the disease. Thus, claims 1, 7, 9 and 10 of Lester 2 and EMA teaching render claim 18 obvious.
Claim 22 of instant application is drawn to formulation comprising rhTPP1 and at least one pharmaceutically acceptable carrier, diluent or excipient. Claim 23 of instant application recites carriers, diluents and excipients. Claim 2 of Lester 2 teaches rhTPP1 composition comprising potassium chloride, magnesium chloride and calcium chloride dehydrate recited in instant claim 23. Thus, claims 1, 2, 9 and 10 of Lester 2 and EMA teachings render claims 22 and 23 obvious.
Claim 24 of instant application is drawn to administering a flush solution after the formulation administration. That corresponds to claim 11 of Lester 2. Thus, claims 1 and 9-11 of Lester 2 and EMA teaching render claim 24 obvious.
Claim 17 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9 and 10 of U.S. Patent No. 11229687 (Lester 1) in view of European Medicine Agency (EMA) (European Medicine Agency, Brineura: ANNEX I Summary of Product Characteristics, 2017, [retrieved on 09/20/2024]. Retrieved from the Internet: <http://ec.europa.eu/health/documents/communityregister/2017/20170530137963/anx_137963_en.p df> on record in IDS) as applied to claim 1 above, and further in view of Lukacs (Lukacs et al. Chimica Clinica Acta, 2019, 492, 69-71).
Instant claim 17 is directed to decrease in TPP1 activity based on blood test.
Lester 2 and EMA teachings have been set forth above.
Lester 2 and EMA do not teach decrease in TPP1 enzyme activity in a subject based on blood test.
Lukacs teaches fluorometric test for TPP1 activity in blood samples to diagnose CNL2 (Title). Test performed on 50 samples from patients with CNL2 confirmed by clinical and molecular genetic data identified decline in CLN2 activity comparing to control samples (Abstract, p. 70, Figure 1). Lukacs mentions: “We consider our TPP1 test on DBS (dried blood samples) to be a reliable, convenient and inexpensive tool for a first diagnostic step in suspected CLN2 disease.” (Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to add teachings of Lukacs to method of treatment of CLN2 patients based on Lester 2 and EMA teachings and perform test for TPP1 activity on blood samples of patients to confirm the diagnosis. One would have been motivated to make this combination because Lukacs teaches test to be reliable and convenient for diagnosing CLN2 disease. A skilled artisan would have reasonably expected success in this combination since Lester 2 and EMA provided formulation and method for treatment of TPP1 deficiency and Lukacs described test for confirmation of TPP1 deficiency by measuring its activity in blood samples. Thus, reference claims 1, 9 and 10, EMA and Lukacs teaching render claim 17 obvious.
Therefore, since instant claims 2, 7, 10-19 and 21-24 encompass the subject matter of the reference claims 1, 2, 7 and 9-11, they are rejected under obviousness double patenting.
Response to Arguments
Applicant's arguments filed 03/12/2026 have been fully considered but they are not persuasive.
Applicant argues (addressing p. 10-11 of the Remarks) that ‘687 patent and ‘598 patent do not disclose treatment of CLN2 patients under 3 years old. EMA provides possible doses for rhTPP1 that could be used in treatment of CLN2 but does not disclose treatment of patients less than 3 years old having total ML score of 3-6. Applicant further argues that administration of rhTPP1 to the mentioned population of patients surprisingly resulted in delayed onset of CLN2 disease or symptoms and that result could not be predicted from EMA or ‘687 and ‘598 patents taken alone or in combination. These arguments are not persuasive because:
Although ‘687 and ‘598 patents do not teach treatment of patients less than 3 years old with the total ML score of 3-6, ‘687 and ‘598 patents and EMA teach instant method steps, i.e. administering rhTPP1; instant formulation, i.e. rhTPP1; instant routes of administration; the same dosage and regimen, i.e. 300 mg every other week and have the same goal of preventing symptoms of CLN2 as instant claim 1. EMA teaches significant delay of the decline of motor and language functions with the treatment of patients with average total ML score of 3.5 (p. 10, 2nd paragraph, Figure 2) and EMA discloses detailed instructions on the dosage for patients of different age categories less than 3 years old and mentions importance of initiation of CLN2 treatment for children as early as possible (p. 3) providing motivation to add EMA instructions to ‘687 and ‘598 patents and treat CLN2 in patients less than 3 years old with total ML score of 3-6 expecting that treatment to delay the onset or symptoms of CLN2 disease.
Conclusion
No claims are allowed.
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/L.G.K./Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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