Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claim Status
Receipt of Remarks/Amendments filed on 12/3/2025 is acknowledged. Claims 70 and 72 are currently pending and presented for examination on the merits for patentability.
Rejection(s) not reiterated from the previous Office Action are hereby withdrawn. The following rejections are either reiterated or newly applied. They constitute the complete set of rejections presently being applied to the instant application.
Withdrawn Rejections/Objections
The objection to specification has been withdrawn due to appropriate amendments to the specification.
New/Maintained Claim Rejections/Objections
New Matter
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 70 and 72 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 70 recites “wherein the myeloproliferative disorder is myelofibrosis, wherein the myelofibrosis is primary myelofibrosis, intermediate risk level 2 myelofibrosis, high risk myelofibrosis, secondary myelofibrosis, post essential thrombocythemia myelofibrosis, and post polycythemia vera myelofibrosis”, which suggests the claim requires administering the claimed compound to a subject having all these myelofibrosis disorders because of “and” recited before “post polycythemia vera myelofibrosis”. While the specification provide support for administering the claimed compound to a subject having one of the claimed myelofibrosis disorders (e.g. either primary myelofibrosis, secondary myelofibrosis such as post essential thrombocythemia myelofibrosis or post polycythemia vera myelofibrosis, intermediate risk level 2 myelofibrosis or high risk myelofibrosis) (see e.g., examples 1-3 of specification), however, the specification do not have any support for administering the claimed compound to a single subject having all these myelofibrosis disorders. For example, secondary myelofibrosis is myelofibrosis arising from other myeloproliferative neoplasms ( polycythemia vera or essential thrombocythemia) whereas primary myelofibrosis occurs without other myeloproliferative neoplasms (see e.g., para 0090 of specification). The instant specification do not provide support for treating a myeloproliferative disorder by administering the claimed compound to a subject having both primary myelofibrosis and secondary myelofibrosis because the examples in the specification disclose a subject having either primary or secondary myelofibrosis, or a subject having intermediate risk level 2 myelofibrosis or high risk myelofibrosis. There is no disclosure in the specification which supports administering the claimed compound to a single subject having all the claimed myelofibrosis disorders.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 70 and 72 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 70 recites “wherein the myeloproliferative disorder is myelofibrosis, wherein the myelofibrosis is primary myelofibrosis, intermediate risk level 2 myelofibrosis, high risk myelofibrosis, secondary myelofibrosis, post essential thrombocythemia myelofibrosis, and post polycythemia vera myelofibrosis”. As discussed supra, this recitation suggests the claim requires administering the claimed compound to a subject having all these myelofibrosis disorders because of “and” recited before “post polycythemia vera myelofibrosis”. It is unclear how a subject being treated for myeloproliferative disorder and being administered the claimed compound has all of the myelofibrosis disorders recited in claim 70. For example, secondary myelofibrosis is myelofibrosis arising from other myeloproliferative neoplasms ( polycythemia vera or essential thrombocythemia) whereas primary myelofibrosis occurs without other myeloproliferative neoplasms (see e.g., para 0090 of specification). It is unclear how a subject can have both primary myelofibrosis and secondary myelofibrosis because if the subject has secondary myelofibrosis (e.g., myelofibrosis arising from other myeloproliferative neoplasms (polycythemia vera or essential thrombocythemia)), then this would exclude primary myelofibrosis because primary myelofibrosis occurs without other myeloproliferative neoplasms. Further, it is unclear how a subject can have both intermediate risk and high risk myelofibrosis because if a subject has high risk myelofibrosis, then this means that the subject is not intermediate risk but rather a high risk myelofibrosis subject. The specification also do not clarify or provide support for administering the claimed compound to a subject having all the claimed myelofibrosis disorders as discussed in the new matter rejection above. As discussed supra, the specification only provide support for administering the claimed compound to a subject having one of the claimed myelofibrosis disorders (e.g. either primary myelofibrosis, secondary myelofibrosis such as post essential thrombocythemia myelofibrosis or post polycythemia vera myelofibrosis, intermediate risk level 2 myelofibrosis or high risk myelofibrosis) (see e.g., examples 1-3 of specification). Therefore, the claim is rendered indefinite because it unclear how a subject being treated for myeloproliferative disorder and being administered the claimed compound has all of the myelofibrosis disorders recited in claim 70.
Claim 72 is included in the rejection as it depends on a rejected base claim and does not clarify the issues discussed above.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 70 and 72 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating a myeloproliferative disorder comprising administering the claimed compound to a subject having one of the claimed myelofibrosis disorders (e.g. either primary myelofibrosis, secondary myelofibrosis such as post essential thrombocythemia myelofibrosis or post polycythemia vera myelofibrosis, intermediate risk level 2 myelofibrosis or high risk myelofibrosis) (see e.g., examples 1-3 of specification), however, it does not reasonably provide enablement for treating a myeloproliferative disorder comprising administering the claimed compound to a single subject having all these myelofibrosis disorders. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
As disclosed by Curtis (What is Myelofibrosis; Health.com), primary myelofibrosis occurs without an underlying blood or bone marrow disorder. Secondary myelofibrosis develops due to an underlying blood or bone marrow disorder (polycythemia vera or essential thrombocytosis) (see entire document). Thus, if a subject has secondary myelofibrosis (e.g., myelofibrosis arising from polycythemia vera or essential thrombocythemia), then this would exclude primary myelofibrosis because primary myelofibrosis occurs without an underlying blood or bone marrow disorder. Blood Cancer UK reference (Prognosis for myelofibrosis, Bloodcancer.org.uk) teaches that in risk scoring for myelofibrosis, doctors come up with a risk score of low, intermediate-1, intermediate-2 or high. This gives doctors an idea of your prognosis and helps them decide what treatment patients need. If the risk score is low or intermediate-1, patient may not need treatment at all. (see entire document). This suggests that patients are classified as either low, intermediate or high risk patients and a patient that is high risk would not be classified as intermediate at the same time. These references suggest that a single subject with myeloproliferative disorder cannot have all of the claimed myelofibrosis disorders (i.e., primary myelofibrosis, intermediate risk level 2 myelofibrosis, high risk myelofibrosis, secondary myelofibrosis, post essential thrombocythemia myelofibrosis, and post polycythemia vera myelofibrosis) at the same time and the specification does not reasonably provide enablement for treating a myeloproliferative disorder comprising administering the claimed compound to a single subject having all of these myelofibrosis disorders.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Formal, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
1) the quantity of experimentation necessary,
2) the amount of direction or guidance provided,
3) the presence or absence of working examples,
4) the nature of the invention,
5) the state of the prior art,
6) the relative skill of those in the art,
7) the predictability of the art, and
8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention and relative skill level
The invention relates to a method of treating a myeloproliferative disorder. The relative skill of those in the art is high, that of an MD or PHD and someone expert in blood disorders and oncology.
The state and predictability of the art
The art however is unpredictable. The art requires utilization of specific anti-cancer agents and other pharmaceutical ingredients which are both safe and effective for treating blood related disorders such as myeloproliferative disorders. For example, as discussed supra, myeloproliferative disorder comes in various forms which can have certain underlying causes (e.g., secondary myelofibrosis) or occur without an underlying cause (e.g., primary myelofibrosis) and have different risk levels which require a specific drug compound in a specific dose/amount to be treated. With the art being unpredictable, the specification needs to provide more details and evidence as to how the claimed method can treat the claimed myeloproliferative disorders comprising administering the claimed compound to a single subject having all these myelofibrosis disorders.
The breadth of the claims
The claim is very broad insofar as it recites wherein the myelofibrosis is primary myelofibrosis, intermediate risk level 2 myelofibrosis, high risk myelofibrosis, secondary myelofibrosis, post essential thrombocythemia myelofibrosis, and post polycythemia vera myelofibrosis. While treating myelofibrosis by administering the claimed compound in a subject having all these claimed myelofibrosis disorders might theoretically be possible, as a practical matter it is nearly impossible to achieve in the “real world” to have a subject having all these claimed myelofibrosis disorders and treating them as evidenced by the references discussed above which suggest a single subject cannot have all these claimed myelofibrosis disorder at the same time.
The amount of direction or guidance provided and the presence or
absence of working examples
The specification provides no direction, guidance or evidentiary data showing how the instantly claimed method result treating a myeloproliferative disorder comprising administering the claimed compound to a single subject having all of the myelofibrosis disorders.
The quantity of experimentation necessary
Because of the known unpredictability of the art, and in the absence of experimental evidence, no one skilled in the art would accept the assertion that the instantly claimed agents could be predictably used to treating a myeloproliferative disorder comprising administering the claimed compound to a single subject having all of the myelofibrosis disorders as inferred by the claim. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Note: For the rejections below, the examiner interprets the claims require the subject to have only one of the claimed myeloproliferative disorder.
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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 70 and 72 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over HOOD et al. (U.S. PG-Pub. No. 2009/0286789)(cited in IDS) in view of MANN et al. (WO 2007/089768 A2)(cited in IDS), PFEFFER et al. (U.S. PG-Pub. No. 2006/0210627 A1)(cited in IDS), PLATTEEUW et al. (WO 2004091585 A1) (cited in IDS), European Medicine Agency (EMA) (European Medicine Agency Science Medicines Health, Orphan designation for treatment of primary myelofibrosis, October 1, 2010), Atallah et al. (Expert Rev Anticancer Ther. 2009 May; 9 (5): 663-670) and Mesa et al. (N Engl J Med, 363;12 September 16, 2010).
HOOD teaches a pharmaceutical composition, which is formulated for oral administration, comprising a therapeutically effective amount of a compound (A), i.e. formula (LVII) which has chemical structure as set forth below (see: [0018]; & Example 90):
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.
As such, the “tablets” or “capsules” read on the “unit dosage form” as claimed; and the “compound of formula (LVII)” taught by HOOD reads on the same compound of claim 70.
HOOD teaches that the composition includes one or more non-toxic pharmaceutically acceptable excipients, e.g. diluents and lubricating agent ([0084]).
HOOD teaches that the compound (A) can be present in a suitable dosage which can be adjusted, depending on the conditions of the patients to be treated (see: [0099]).
HOOD et al. teach the treatment of conditions which involve cellular proliferation, which can be administered in a single dose at 400 mg active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compound can be administered on a regimen 1 time per day (page 33, paragraph 99). HOOD et al. teaches the compound is used to treat myeloproliferative disorders and specifically myeloid fibrosis (myelofibrosis) (page 30, paragraph 73).
HOOD teaches that the compound of formula (LVII) can be in free base (neutral) form, but which can be converted into hydrochloride salts by reacting the neutralized compound (A) with HCl solution to form the 2,4-diamine hydrochloride salt (see: e.g. [0227-0228]). As such, it reads on the “dihydrochloride” form of the claimed compound.
HOOD teaches a composition comprising the same compound as claimed admixed with one or more non-toxic pharmaceutically acceptable excipients, e.g. diluent and lubricating agent as claimed. HOOD also teaches that the compound, i.e. formula (LVII) is an inhibitor of JAK kinase and specifically a JAK2 inhibitor (see: ABSTRACT; Para 0752). However, HOOD does not teach: (i) the weight ratio of the compound and filler/diluent as recited in instant claims; and also does not teach the amount of lubricating agent as recited in instant claims. The deficiencies are taught by the reference MANN and PFEFFER et al.
MANN teaches a pharmaceutical composition comprising inhibitors of JAK-2 for treating a disease mediated by JAK-2, and MANN teaches that the inhibitors of JAK-2 can be converted from its free base form to hydrochloride salt (HCl-salt form) with HCl acid (see: [0191]; [0208]). This teaching is similar to the teaching provided by HOOD.
MANN teaches that the composition, which contains JAK-2 inhibitors as active, can be formulated into a dosage for oral administration (see: [0132]) and comprises suitable pharmaceutical excipients or diluents, i.e. suspending agents (e.g. microcrystalline cellulose); binders (e.g. cellulose derivatives); lubricants (e.g. magnesium stearate, sodium lauryl sulfate) (see: [0133]; [0136]; [0138]).
The other reference PFEFFER teaches a method to prepare a pharmaceutical formulation, i.e. comprises a DPP-IV inhibitor, wherein the formulation is capable of being directly compressed into tablets by inclusion of desirable excipients to provide improved properties, e.g. high-compressibility to allow strong tablets to be made at low compression forces; good flow properties that can improve the flow of other excipients in the formula; and cohesiveness to prevent tablet from crumbling during processing, shipping and handling (see: [0069-0071]).
PFEFFER teaches that the desirable excipients include various diluents, binders, disintegrant, lubricants (see: [0060]), wherein one or more filler and/or diluent can be used, e.g. microcrystalline cellulose can be used in an amount, e.g. preferably about 70 % by weight (see: [0094]). As such, the “microcrystalline cellulose” as filler and diluent reads on the same filler/diluent and its amount, as recited in instant claims.
PFEFFER teaches that the one or more lubricant can be used, e.g. magnesium stearate in an amount, i.e. preferably about 0.1% to about 2% by weight (see: [0097]). As such, the “lubricant” and its amount suggested by PFEFFER reads on the present “lubricant and its amounts” as recited in instant claims.
PFEFFER teaches that, preferably, the active can be included in 20-35% by weight on a dry weight basis in free form or in acid addition salt form (see: [0139]). As such, if the active is used in “about 35 % by weight” and the filler and/or diluent (e.g. microcrystalline cellulose) is used in an amount of “about 70 %” by weight, the weight ratio between the active and the filler/diluent would be 1:2. As such, said ratio reads on the similar weight ratio, i.e. 1:2, of the active compound and the filler/diluent as claimed can be used in order to obtain the desirable and improved formulation properties as discussed above. Thus, the weight ratio of the active compound and the filler/diluent, as recited in instant claims, are met.
The combination of HOOD, MANN and PFEFFER teaches all elements, i.e. the compound of (i); the filler/diluent and its weight ratio to the compound; and the lubricant. However, the cited references do not teach the specific microcrystalline cellulose (e.g. silicified microcrystalline cellulose) and lubricant (e.g. sodium stearyl fumarate), as recited in instant claims. The deficiency is taught by the reference PLATTEEUW et al.
PLATTEEUW teaches an oral dosage form using silicified microcrystalline cellulose (SMC) as the filler/diluent (see: Abstract), and the advantage of using the silicified form as it offers enhanced compressibility for forming drug tablet (see: page 3). As such, the “silicified microcrystalline cellulose” reads on the claimed microcrystalline cellulose, as recited in the instant claims.
PLATTEEUW also teaches examples of tablet containing, e.g. 10 mg of an active and 49 mg of silicified microcrystalline cellulose (see: page 25, Table 8: Example 10), which provides an active to SMC weight ratio of about 1:5 and it reads on the claimed weight ratio, as recited in the instant claims.
PLATTEEUW also teaches the use of “sodium stearyl fumarate” as the lubricant in the oral dosage form, and the advantage of such lubricant is that it tends to facilitate faster disintegration rate (see: page 9). As such, the “sodium stearyl fumarate” reads on the claimed lubricant, as recited in the instant claims.
PLATTEEUW also teaches using 1.05 mg of sodium stearyl fumarate with a total tablet weight of 70 mg (which is 1.4% w/w) in Example 16 (see: page 25, Table 8). As such, said lubricant amount falls in the claimed amount, as recited in the instant claims.
As discussed supra, Hood et al. teaches the compound is used to treat myeloproliferative disorders and specifically myeloid fibrosis (myelofibrosis) (page 30, paragraph 73). Hood also teaches that the compound, i.e. formula (LVII) is an inhibitor of JAK kinase and specifically a JAK2 inhibitor (see: ABSTRACT; Para 0752). Hood does not expressly teach the compound is used to treat the specific types of myelofibrosis disorders recited in instant claims. However, EMA, Atallah and Mesa references cure this deficiency.
EMA teaches a JAK2 inhibitor drug which is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate (fedratinib), which is the same as the compound recited in instant claims. EMA teaches orphan designation of fedratinib had been granted in the United States for the treatment of both secondary and primary myelofibrosis. (see: entire document).
Atallah throughout the reference discloses treatment of myelofibrosis disorders with different JAK2 inhibitors. Attallh teaches TG101348 (fedratinib) being effective in reducing spleen size in patients with primary myelofibrosis, post polycythemia vera myelofibrosis and post essential thrombocythemia myelofibrosis. Atallah teaches that with JAK2 inhibitors, marked clinical improvement has been seen in patients on therapy, with significant decrease in spleen size and improved quality of life (see: page 3 and 7).
Mesa also throughout the reference teaches use of JAK 1 and JAK2 inhibitors in treatment of myelofibrosis. Mesa teaches that JAK1 and JAK2 inhibitor was associated with clinical benefits in patients with advanced (intermediate-2 or high risk) myelofibrosis. (see: abstract; discussion).
It would have been obvious to a person of ordinary skilled in the art at the time the invention was made to combine the compound of formula (LVII) taught by HOOD with the desirable pharmaceutically excipients, i.e. filler/diluent (e.g. microcrystalline cellulose) and lubricant in a suitable amount as taught by MANN and PFEFFER, because MANN and PFEFFER teach that the composition containing JAK-2 inhibitors as active can be formulated into a dosage for oral administration by adding suitable pharmaceutical excipients or diluents, i.e. suspending agents (e.g. microcrystalline cellulose); binders (e.g. cellulose derivatives); lubricants; and PFEFFER teaches that pharmaceutical formulation comprising active agent can be formulated to be capable of being directly compressed into tablets by including desirable excipients, e.g. microcrystalline cellulose (as filler/diluent) and lubricants, to provide improved properties, e.g. high-compressibility to allow strong tablets to be made at low compression forces; good flow properties that can improve the flow of other excipients in the formula; and cohesiveness to prevent tablet from crumbling during processing, shipping and handling. Therefore, it would have been obvious to one skilled in the art to manipulate and optimize the amounts of the lubricant and filler/diluent, and the ratio of the active compound to filler/diluent during routine experimentation to obtain the desired properties when formulation a unit dose such as a tablet.
With respect to the Cmax recited in the instant claims, it would have been obvious to one of ordinary skill in the art at the time of invention to use the teachings of Hood et al. and know that the compound of formula (LVII) would provide a Cmax as currently claimed. It would have been obvious to one of ordinary skill in the art at the time of the invention that the compound taught by Hood et al., is the same compound that is currently claimed. As such, following the prior art teaching that if the same compound/composition (Compound LVII) that is used in a method of treating myeloproliferative disorder such as myeloid fibrosis (myelofibrosis) comprising the administration to a subject in need thereof a therapeutically effective amount (400 mg as taught by Hood et al.) of compound represented by
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or its pharmaceutically acceptable salts or N-oxides is taught in the prior art, the skilled artisan would expect to obtain a result that necessarily flows with the intended purpose and properties, a formulation that provides a steady state patient Cmax of the compound that is achieved within 2 to 4 hours post administration; and/or a steady state patient Cmax of the compound between 1717.33 ng/mL and 3886.67 ng/mL post administration, without evidence to the contrary.
With respect to the instantly claimed limitation wherein the formulation is administered daily at 400 mg dose, Hood discloses an amount which overlaps the claimed dose and it would have been obvious to one skilled in the art to manipulate the dose during routine optimization and such a dose would be dependent upon parameters which include age, gender, size, etc. of the patient population. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
With regards to wherein the compound is dihydrochloride monohydrate, as discussed supra, Hood teaches that the compound of formula (LVII) can be in free base (neutral) form, but which can be converted into hydrochloride salts by reacting the neutralized compound (A) with HCl solution to form the 2,4-diamine hydrochloride salt (see: e.g. (0227-0228)). As such, it reads on the “dihydrochloride” form of the claimed compound. Further, Hood teaches the compound can include a pharmaceutically acceptable salts or hydrate thereof (para 0019), EMA teaches a JAK2 inhibitor drug which is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate (fedratinib), and absence any criticality of the claimed salt, it would have been obvious to include the claimed compound in the form of a dihydrochloride monohydrate.
It would have been obvious to a person of ordinary skilled in the art at the time the invention was made to substitute PFEFFER’s filler/diluent and lubricant with another suitable filler/diluent and lubricant, i.e. the silicified microcrystalline cellulose as filler/diluent and sodium stearyl fumarate as lubricant taught by PLATTEEUW, because PLATTEEUW teaches the advantage of using the silicified form as it offers enhanced compressibility for forming drug tablet and the advantage of using sodium stearyl fumarate as lubricant is that it helps to facilitate faster disintegration rate when forming drug tablet. Therefore, one ordinary skilled in the art would have recognized that the advantages provided by said silicified microcrystalline cellulose (as filler/diluent) and sodium stearyl fumarate (as lubricant) are desirable and said would have motivated one ordinary skilled in the art to substitute the silicified microcrystalline cellulose and sodium stearyl lubricant for those filler/diluent and lubricant taught by PFEFFER.
It would have been obvious to a person of ordinary skilled in the art at the time the invention was made to have used the compound and composition taught by Hood for treating the specific types of myelofibrosis disorders recited in instant claims, based on the teachings of EMA, Atallah and Mesa references. As discussed supra, Hood et al. teaches the compound is used to treat myeloproliferative disorders and specifically myeloid fibrosis (myelofibrosis) (page 30, paragraph 73). Hood also teaches that the compound, i.e. formula (LVII) is an inhibitor of JAK kinase and specifically a JAK2 inhibitor (see: ABSTRACT; Para 0752). EMA teaches orphan designation of fedratinib had been granted in the United States for the treatment of both secondary and primary myelofibrosis. Atallah teaches that with JAK2 inhibitors (including fedratinib), marked clinical improvement has been seen in patients on therapy, with significant decrease in spleen size and improved quality of life in patients with primary myelofibrosis, post polycythemia vera myelofibrosis and post essential thrombocythemia myelofibrosis. EMA and Atallah teach the same compound/drug as taught by Hood for treatment of myelofibrosis and specifically, primary myelofibrosis, secondary myelofibrosis, post polycythemia vera myelofibrosis and post essential thrombocythemia myelofibrosis. Therefore, it would have been obvious to one skilled in the art to use the compound/composition of Hood for treatment of the specific types of myelofibrosis disorders.
Further, as discussed supra, Mesa throughout the reference teaches use of JAK 1 and JAK2 inhibitors in treatment of myelofibrosis. Mesa teaches that JAK1 and JAK2 inhibitor was associated with clinical benefits in patients with advanced (intermediate-2 or high risk) myelofibrosis. Hood also teaches that the compound, i.e. formula (LVII) is an inhibitor of JAK kinase and specifically a JAK2 inhibitor which is used to treat myelofibrosis. Therefore, one skilled in the art would have been motivated to utilize the compound/composition of Hood for treating patients with advanced (intermediate-2 or high risk) myelofibrosis because Mesa teaches JAK2 inhibitors are associated with clinical benefits in patients with advanced (intermediate-2 or high risk) myelofibrosis.
Therefore, from the combined teaching of the references, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Response to Arguments
Applicant argued that EMA, Atallah and Mesa references may allude to these specific disorders but there is no teaching, suggestion or motivation in these references to combine these references to include the specific disorders with this specific compound.
In response, EMA teaches orphan designation of fedratinib had been granted in the United States for the treatment of both secondary and primary myelofibrosis. Atallah teaches that with JAK2 inhibitors (including fedratinib), marked clinical improvement has been seen in patients on therapy, with significant decrease in spleen size and improved quality of life in patients with primary myelofibrosis, post polycythemia vera myelofibrosis and post essential thrombocythemia myelofibrosis. EMA and Atallah teach the same compound/drug as taught by Hood for treatment of myelofibrosis and specifically, primary myelofibrosis, secondary myelofibrosis, post polycythemia vera myelofibrosis and post essential thrombocythemia myelofibrosis. Therefore, it would have been obvious to one skilled in the art to use the compound/composition of Hood for treatment of the specific types of myelofibrosis disorders.
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).
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Claims 70 and 72 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 10,391,094 B2 in view of HOOD et al. (U.S. PG-Pub. No. 2009/0286789), European Medicine Agency (EMA) (European Medicine Agency Science Medicines Health, Orphan designation for treatment of primary myelofibrosis, October 1, 2010), Atallah et al. (Expert Rev Anticancer Ther. 2009 May; 9 (5): 663-670) and Mesa et al. (N Engl J Med, 363;12 September 16, 2010).
The instant claims are drawn to a method of treating myeloproliferative disorder comprising administering to a subject in need thereof a unit dosage form comprising:
(i) a compound:
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or a pharmaceutically acceptable salt and/or hydrate thereof (e.g. a dihydrochloride monohydrate);
(ii) one or more fillers and/or diluents (e.g. microcrystalline cellulose, which is silicified microcrystalline cellulose);
wherein the ratio of the weight of the compound to the total weight of the one or more fillers and/or diluents is about 1:1.5 to about 1:9, or about 1:1.5 to about 1:2; and
(iii) about 0.5% to about 5% w/w of one or more lubricants (e.g. sodium stearyl fumarate);
Wherein the unit dosage form provides, when administered at 400 mg total daily dose of the compound, a Cmax that is achieved within 2 to 4 hours post administration; and/or a Cmax between 1717.33 ng/mL and 3886.67 ng/mL;
Wherein the myeloproliferative disorder is myelofibrosis, primary myelofibrosis, intermediate-2 myelofibrosis, high risk myelofibrosis, secondary myelofibrosis, post essential thrombocythemia myelofibrosis and post polycythemia vera myelofibrosis.
The conflicting claims are drawn to a method of treating myelofibrosis in a subject comprising administering a capsule comprising a formulation comprising:
(i) a compound that is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzene-sulfonamide dihydrochloride monohydrate;
(ii) a microcrystalline cellulose (e.g. silicified microcrystalline cellulose); and
(iii) sodium stearyl fumarate, which is present about 1% by weight of the formulation;
wherein the weight ratio of the N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide to the microcrystalline cellulose in the formulation is about 1:1.5 to about 1:9, or 1:1.5 to about 1:2.
It is noted that the conflicting application defined that “, the unit dosage form is in the form of a capsule” (see Pat “094: col. 2, line 51-52). As such, the conflicting “capsule” reads on the “unit dosage form” as claimed.
It is noted that the above compound in the conflicting claims has a chemical structure as set forth below, which reads on the compound and its dihydrochloride monohydrate as claimed:
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and
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.
In addition, the “microcrystalline cellulose” and “silicified microcrystalline cellulose” in the conflicting claims, as well as its “weight ratio to the conflicting compound” read on the “filler or diluent comprises microcrystalline cellulose, which is silicified microcrystalline cellulose” as claimed.
Further, the “sodium stearyl fumarate which is present in about 1% by weight” reads on the “lubricant and its amount present in the unit dosage (e.g. in the range from about 0.5% to 5%, or about 0.5% to about 2% by weight or about 1% by weight), comprises sodium stearyl fumarate” as claimed.
The ‘094 patent does not teach Wherein the unit dosage form provides, when administered at 400 mg total daily dose of the compound, a Cmax that is achieved within 2 to 4 hours post administration; and/or a Cmax between 1717.33 ng/mL and 3886.67 ng/mL. However, Hood et al. cures this deficiency.
The teachings of Hood et al. set forth above are incorporated herein. As discussed supra, HOOD et al. teach the treatment of conditions which involve cellular proliferation, which can be administered in a single dose at 400 mg active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compound can be administered on a regimen 1 time per day (page 33, paragraph 99). HOOD et al. teaches the compound (which is the same as the instantly claimed compound in claim 70 (i)) is used to treat myeloproliferative disorders and specifically myeloid fibrosis (myelofibrosis) (page 30, paragraph 73).
The ’094 patent also does not expressly teach Wherein the myeloproliferative disorder is myelofibrosis, primary myelofibrosis, intermediate-2 myelofibrosis, high risk myelofibrosis, secondary myelofibrosis, post essential thrombocythemia myelofibrosis and post polycythemia vera myelofibrosis. However, EMA, Atallah and Mesa references cure this deficiency.
The teachings of EMA, Atallah and Mesa set forth above are incorporated herein.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to combine the teachings of ‘094, Hood, EMA, Atallah and Mesa and administer the drug/compound (fedratinib) taught by ‘094 and Hood at a dose of 400 mg as suggested by Hood. Both Hood and ‘094 teach the same compound for treating the same condition (myelofibrosis) and thus, it would have been obvious to a skilled artisan to utilize a dosage (i.e., 400 mg) which is taught and known in the art as suggested by Hood.
With respect to the Cmax recited in the instant claims, it would have been obvious to one of ordinary skill in the art at the time of invention to use the teachings of Hood et al. and know that the compound of formula (LVII) would provide a Cmax as currently claimed. It would have been obvious to one of ordinary skill in the art at the time of the invention that the compound taught by ‘094 and Hood et al., is the same compound that is currently claimed. As such, following the prior art teaching that if the same compound/composition (Compound LVII) that is used in a method of treating myeloproliferative disorder such as myeloid fibrosis (myelofibrosis) comprising the administration to a subject in need thereof a therapeutically effective amount (400 mg as taught by Hood et al.) of the compound taught in the prior art, the skilled artisan would expect to obtain a result that necessarily flows with the intended purpose and properties, a formulation that provides a steady state patient Cmax of the compound that is achieved within 2 to 4 hours post administration; and/or a steady state patient Cmax of the compound between 1717.33 ng/mL and 3886.67 ng/mL post administration, without evidence to the contrary.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to combine the teachings of ‘094, Hood, EMA, Atallah and Mesa and have used the compound and composition taught by ‘094 for treating the specific types of myelofibrosis disorders recited in instant claims. As discussed supra, ‘094. teaches the compound is used to treat myelofibrosis. Hood teaches that the compound, i.e. formula (LVII) is an inhibitor of JAK kinase and specifically a JAK2 inhibitor (see: ABSTRACT; Para 0752). EMA teaches orphan designation of fedratinib had been granted in the United States for the treatment of both secondary and primary myelofibrosis. Atallah teaches that with JAK2 inhibitors (including fedratinib), marked clinical improvement has been seen in patients on therapy, with significant decrease in spleen size and improved quality of life in patients with primary myelofibrosis, post polycythemia vera myelofibrosis and post essential thrombocythemia myelofibrosis. EMA and Atallah teach the same compound/drug as taught by ‘094 for treatment of myelofibrosis and specifically, primary myelofibrosis, secondary myelofibrosis, post polycythemia vera myelofibrosis and post essential thrombocythemia myelofibrosis. Therefore, it would have been obvious to one skilled in the art to use the compound/composition of ‘094 for treatment of the specific types of myelofibrosis disorders.
Further, as discussed supra, Mesa throughout the reference teaches use of JAK 1 and JAK2 inhibitors in treatment of myelofibrosis. Mesa teaches that JAK1 and JAK2 inhibitor was associated with clinical benefits in patients with advanced (intermediate-2 or high risk) myelofibrosis. Hood teaches that the compound, i.e. formula (LVII) is an inhibitor of JAK kinase and specifically a JAK2 inhibitor which is used to treat myelofibrosis. Therefore, one skilled in the art would have been motivated to utilize the compound/composition of ‘094 for treating patients with advanced (intermediate-2 or high risk) myelofibrosis because Mesa teaches JAK2 inhibitors are associated with clinical benefits in patients with advanced (intermediate-2 or high risk) myelofibrosis.
Therefore, from the combined teaching of the cited references, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Response to Arguments
Applicant stated double patenting rejection will be addressed upon allowance. Since applicant have not provided any substantial arguments, double patenting rejection is maintained.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/A.S/ Examiner, Art Unit 1616
/SUE X LIU/ Supervisory Patent Examiner, Art Unit 1616