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 .
Election/Restrictions
Applicant’s election of Group (I) with the addition of Chronic obstructive pulmonary disease (COPD) in the reply filed on 08/18/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 2, 9, 10, 14-16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Priority
This application claims the benefit of priority of: United Kingdom patent application number 2005519.0, filed 16 April 2020; and United Kingdom patent application number 2005520.8, filed 16 April 2020; and US provisional application US 62/706,195, filed4 August 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/10/2022, 12/12/2022, 05/25/2023, 11/07/2023, 04/11/2024, 06/12/2024, 07/08/2024, 08/27/2024, 10/16/2024, 04/21/2025, & 07/04/2025 has been considered by the examiner.
Claim Status
Claims 1, 2, 8-19, and 22-29 are pending. Claims 2-7 and 20-21 are canceled. Claims 2, 9, 10, 14-16 are withdrawn. Claims 1, 8, 11-13, 17-19, and 22-29 are examined in accordance to the elected species.
Claim Objections
Claims 1 and 22 are objected to because of the following informalities: The recitation of “the twice daily oral administration …” recited in claim 1 should be “a twice daily oral administration….” because the article “the” is intended to refer back to an element that has already been introduced and in this case, no previous twice daily oral administration has been recited.
The recitation of a-1 antitrypsin deficiency recited in claims 1 and 22 should be α-1 antitrypsin deficiency. The recitation of AAT therapy should be replaced with α-1 antitrypsin deficiency (AAT) therapy.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 8, 11, 12, 13, 18, 19, and 25-29 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 1 recites the limitation "the twice daily oral administration of a single or multiple solid dosage form(s)" in line 2 of claim because the word “the” is intended to refer back to an element that has already been introduced and in this case, no previous twice daily oral administration has been recited. There is insufficient antecedent basis for this limitation in the claim.
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.
Claims 28 and 29 are 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. Both claims 28 and 29 depend from claim 1. The recitation of wherein 120 mg … in claim 28 and wherein 240 mg … in claim 29 fail to further limit the total of 120-300 mg recited in claim 1 because claim 1 requires 120-300 mg to be total amount whereas the broad limitation of 120 mg in claim 28 and the broad limitation of 240 mg in claim 29 are not the total. 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.
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 1, 8, 11-13, 17-19, and 22-29 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 COPD, does not reasonably provide enablement for all the diseases of the respiratory system mediated by alpha-1 antitrypsin deficiency. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. This is a scope of Enablement
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue."
In In re Wands, 8 USPQ2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have need described. They are:
1. The nature of the invention
2. The state of the prior art
3. The predictability or lack thereof in the art
4. The amount of direction or guidance present
5. The presence or absence of working examples
6. The breadth of the claims
7. The quantity of experimentation needed, and
8. The level of skill in the art
The Nature of the Invention
The instant invention is drawn to a method for treating a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency". Claim 12 further limits the disease, "said disease of the respiratory system which is mediated by a-1 antitrypsin deficiency is selected from the group consisting of asthma, chronic obstructive pulmonary disease COPD, bronchitis, emphysema, bronchiectasis, cystic fibrosis, sarcoidosis, farmer's lung, hypersensitivity pneumonitis, adult respiratory distress syndrome (ARDS), lung fibrosis, tuberculosis, aspergillosis, antitussive activity, iatrogenic cough, acute and chronic rhinitis, acute viral infection, pulmonary hypertension, infection due to respiratory syncytial virus, influenza, coronavirus, and adenovirus"
The Level of Skill in the Art and the Predictability or lack thereof in the art
With respect to respiratory disease; Jonathan Robert Caronia, (Restrictive lung disease, October 31, 2016) teaches because of a lack of response to available anti-inflammatory therapy, alternative approaches to therapy are being pursued; emerging strategies to treat patients with IPF (idiopathic pulmonary fibrosis) include agents that inhibit epithelial injury or enhance repair, anticytokine approaches, agents that inhibit fibroblast proliferation or induce fibroblast apoptosis, and other novel approaches. (See page 2 first paragraph.) Moreover, Jonathan Robert Caronia teaches corticosteroids are a first-line therapy but are associated with myriad adverse effects; corticosteroids, the most commonly used drugs, halt or slow the progression of pulmonary parenchymal fibrosis with variable success. Questions about which patients should be treated, when therapy should be started, what constitutes the best therapy receive uncertain answers at present. (See page 2, second and third paragraph.)
Polverino et al (Chest, Volume 152, Issue 2, August 2017, Pages 249-262) teaches in many respiratory diseases characterized by an intense inflammatory response, the balance between proteolytic enzymes (proteases, including elastases) and their inhibitors (proteinases inhibitors) is not neutral. Excess activity of neutrophil elastase (NE) and similar proteases has been reported to cause tissue damage and to alter the remodeling process in many clinical conditions such as pneumonia, respiratory distress, and acute lung injury (ALI). Several experimental NE inhibitors have been tested in preclinical and clinical studies of different conditions of inflammatory lung injury such as ALI and pneumonia, with contrasting results. This study reviews the literature regarding NE inhibitors in the field of respiratory diseases and reflects on possible future developments. In particular, we highlight potential gaps in the scientific evidence and discuss potential strategies for focusing investigation on antielastases in clinical practice through the selection of targeted populations and proper outcomes. (See Abstract.) Moreover, Polverino teaches the wide variability observed between animal and human studies suggests that more targeted investigations are needed in the future. Many factors, such as patients’ baseline conditions, underlying causes of ALI and ARDS, ventilation mode, comedication, and fluid therapy management, can influence final outcomes in this fragile population. (See last paragraph of the right column of page 259 bridging first paragraph of the left column of page 260.)
In summary, Polverino teaches neutrophil elastase (NE) inhibitors have faced clinical failure due to a combination of factors, including off-target effects, poor bioavailability in the lungs, patient variability, and limitations in clinical trial design. While animal studies show promise and some drugs like sivelestat are used in specific regions, large-scale clinical trials for diseases like acute respiratory distress syndrome (ARDS) have yielded inconsistent or negative results, leading to a lack of global consensus on their efficacy.
Bhatti et al (Ann Thorac Med. 2013 Apr-Jun; 8(2): 71–77) teaches several serum biomarkers have been studied including Annexin-1, which has been detected in 47% of the sera and 53% of the BAL fluid from patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPE). However, there is not enough data to justify the widespread use of these tests, see Section under Biomarkers. Moreover, Bhatti et al teaches currently, there is no definitive long-term treatment proven effective for IPF and there is even less data on prevention and treatment of AE-IPF. (See page 2, second paragraph.)
The instant compounds are disclosed to compound having neutrophil elastase inhibitory activity and said compound is presumed to be predictive of treating any or all diseases of the respiratory tract mediated by alpha-1 antitrypsin deficiency for which applicants provide no competent evidence. It appears that the applicants are asserting that the embraced compounds because of their mode action as net neutrophil inhibitor would be useful for all sorts of respiratory tract mediated by alpha-1 antitrypsin deficiency including the ones recited in claim 12. However, the applicants have not provided any competent evidence that the instantly disclosed tests are highly predictive for all the uses disclosed and embraced by the claim 12 language for the intended host. Moreover, many diseases such as respiratory diseases are very difficult to treat.
No compound has ever been found to treat all types of respiratory tract disease generally. Since this assertion is contrary to what is known in medicine, proof must be provided that this revolutionary assertion has merits. The existence of such a “compound” is contrary to our present understanding of oncology. CCFA, (Treatment Options in IBD (inflammatory bowel disease), May 30, 2012) teaches although there are five basic categories of medications in the treatment of IBD, the fact of the matter is that there is no single ideal therapy for IBD- treatment must be tailored to each person's needs; a number of factors will determine which treatments are appropriate for you—including which part of your intestine is affected, the severity of your symptoms, and whether you are able to take certain drugs without experiencing undesirable side effects. Finally, it's important to keep in mind that your therapeutic needs may change over time. What works at one point during your illness may not be effective during another stage. Clearly, it is important for you and your physician to discuss thoroughly which course of therapy is best for you—bearing in mind that a combination of therapies may well turn out to be the optimal treatment plan, see page 1, last para bridging page 2 para 1 and 2. In sum, the state of the art is indicative of the requirement for undue experimentation. See all of the above cited references. Note all these references state not one single PDE4 inhibitors are effective for treating, ameliorating all of the recited diseases/conditions.
Therefore, there may be various possible adverse effects when a PDE4 inhibitor is given to a patient to treat any of the aforementioned diseases. Much experimentation and in vivo testing must be carried out to make sure that the administration of the compounds of formula (I) results in enhanced therapeutic effects without harmful side effects.
Hence, in the absence of showing of correlation between all the diseases claimed as capable of treatment with a useful mechanism of action with reduced toxicity and anti-inflammatory activity, one of skill in the art is unable to fully predict possible results from the administration of the compounds of formula (I) due to the unpredictability of the role of the instantly claimed compounds.
Applicant's disclosure does not enable one of ordinary skill in the art to use the claimed invention within the entire scope of treating diseases listed above. There is no compound, let alone an entire class of compounds that can treat the various diseases encompassed by the claim, as claimed by various mode of action is still exploratory and requires further experimentation.
The Amount of Direction or Guidance Present
The presence or absence of working examples: Specification has no working examples to show treating all respiratory disease mediated by alpha-1 antitrypsin deficiency diseases recited in the claim, started above and the state of the art is that the treatment of all types of respiratory tract disease are unpredictable. However, the instant specification shows that Nalidixic acid is effective for treating asthma as the only working example.
A disclosure should contain representative examples which provide reasonable assurance to one skilled in the art that the compounds which fall within the scope of a claim will have the alleged activity. The only direction or guidance present in the specification is the listing of inflammatory conditions applicant considers treatable. Receptor activity is generally unpredictable and a highly structure specific area, and the data provided is insufficient for one of ordinary skill in the art to extrapolate to the other compounds of the claims.
The disclosure does not provide how this in vitro data correlates to the treatment of the asserted diseases claimed. The instant specification is short of any examples or data in regards to the supposed treating of the aforementioned all of the diseases of the respiratory system. Applicants have not provided any competent evidence or disclosed tests that are highly predictive for the pharmaceutical use of the instant compounds. Pharmacological activity in general is a very unpredictable area. Note that in cases involving physiological activity such as the instant case, "the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved." See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Consequently, the disclosure does not show any evidence as to whether the claimed compounds are effective for treating all types target. As it is known in the art that neutrophil elastase inhibitors have different functional outcomes depending on where in the cell the targeted alpha-1 antitrypsin deficiency are located and also the importance of the inhibitor with respect to the efficacy.
The Breadth of the Claims
The scope of the claims involves alevelstat or a pharmaceutically acceptable salt thereof for treating of the diseases stated above.
No compound has ever been found to treat respiratory diseases of all types generally. Since this assertion is contrary to what is known in medicine, proof must be provided that this revolutionary assertion has merits. The existence of such a “compound” is contrary to our present understanding of modern medicine. Thus, it is beyond the skill of clinician today to get an agent to be effective against cancers generally. Again, it is beyond the skill of clinician today to get an agent to be effective against all recited diseases. Also see the PTO website
<<http ://www.uspto.gov/web/offices/pac/dapp/1 pecba.htm#7>>
ENABLEMENT DECISION TREE, Example F, situation 1) which is directed to the scope of cancers.
Also, note MPEP 2164.08(b) which states that claims that read on "... significant numbers of inoperative embodiments would render claims non-enabled when the specification does not clearly identify the operative embodiments and undue experimentation is involved in determining those that are operative.” Clearly that is the case here.
Note substantiation of utility and its scope is required when utility is “speculative”, “sufficiently unusual” or not provided. See Ex parte Jovanovics, 211 USPQ 907, 909; In re Langer 183 USPQ 288. Also note Hoffman v. Klaus 9 USPQ 2d 1657 and Ex parte Powers 220 USPQ 925 regarding type of testing needed to support in vivo uses.
Next, applicant’s attention is drawn to the Revised Utility and Written Description Guidelines, at 66 FR 1092-1099, 2001 wherein it is emphasized that ‘a claimed invention must have a specific and substantial utility’. The disclosure in the instant case is not sufficient to enable the instantly claimed method treating solely based on the inhibitory activity disclosed for the compounds.
The Quantity of Experimentation Needed
The quantity of experimentation needed is undue experimentation. It would be an undue burden to one skilled in the pharmaceutical arts since there is inadequate guidance given to the skilled artisan, regarding the pharmaceutical use, for the reasons stated above. One of skill in the art would need to determine what disease out of the multitude claimed would be benefited (i.e. treated) by the administration of alvelestat or a pharmaceutically acceptable salt thereof would furthermore provide treatment of all of the diseases of respiratory system including the disease in claim 12.
Thus, factors such as “sufficient working examples”, “the level of skill in the art” and “predictability”, etc. have been demonstrated to be sufficiently lacking in the instant case for the instant method claims. In view of the breadth of the claims, the chemical nature of the invention, the unpredictability of enzyme-inhibitor interactions in general, and the lack of working examples regarding the activity of the claimed compounds towards treating the variety of diseases claimed in the instant claims, one having ordinary skill in the art would have to undergo an undue amount of experimentation to use the instantly claimed invention commensurate in scope with the claims. Genentech Inc. v. Novo Nordisk A/S (CA FC) 42 USPQ2d 1001, states that "a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion" and "[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable".
Therefore, in view of the Wands factors and in re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation to test which disease can be treated by the compound of the instant claims, with no assurance of success.
MPEP §2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was 'filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here and undue experimentation will be required to practice Applicants' invention.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 12, 13, 17, and 25-29 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by NCT03679598 (National Library of Medicine, Clinical Trial.gov ID, Version 2, 09/22/2018, https://clinicaltrials.gov/study/NCT03679598?tab=history&a=2#version-content-panel)
NCT03679598 teaches a method of treating COPD, the method comprising administering 4 tablets of 30 mg each for a total of 120 mg Alvelestat (MPH996) twice daily to a patient in need thereof. (See “Study Description” and “Arms and interventions” sections.) Alvelestat (or MPH996) is the same as the claimed compound. The 4 tablets meet the claimed multiple oral dosage forms. The total 120 mg and 240 taught by NCT03679598 meets the limitation of claim 28 due to the interpretation sets forth in the 112b rejection above.
With respect to the following limitations: “the Cmin plasma concentration of at least 300 nM in said patient” in claim 25, the Cmax plasma concentration of at least 1000 nM in said patient” in claim 26, and “the Cmin plasma concentration of at least 300 nM and a Cmax plasma concentration of at least 1000 nM in said patient” in claim 27; these limitations simply express the intended outcome of the method step positively recited. Since the claimed method step positively recited is taught by NCT03679598, said intended outcome flow naturally from the method of National Library of Medicine.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 8, 11, 12, 13, 17, 18, 19, 22, and 25-29 are rejected under 35 U.S.C. 103 as being unpatentable over NCT03679598 (National Library of Medicine, Clinical Trial.gov ID, Version 2, 09/22/2018, https://clinicaltrials.gov/study/NCT03679598?tab=history&a=2#version-content-panel ) in view of Alcaraz et al (WO2010/094964 A1) and Tov (US10,960,062 B2).
The teachings of NCT03679598 have been discussed supra.
NCT03679598 does not teach tosylate salt of alevelestat. Moreover, NCT03679598 does not teach minimum total daily dose of 480 mg (claim 11), 440 mg (claim 18), and 360 mg (claim 19). Furthermore, NCT03679598 does not teach a patient that has not responded to previous AAT therapy.
Alcaraz teaches 6-methyl-5-(l-methyl-lH-pyrazol-5-yl)-N-{[5-(methylsulfonyl) pyridin- 2-yl] methyl}-2-oxo-1-[3-(trifluoromethyl) phenyl]-1 ,2-dihydropyridine-3-carboxamide as compound 1
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as the free base is poorly soluble and predictions indicated that the compound (administered as the free base) would demonstrate solubility limited absorption at high doses (for example doses greater than approximately 10 to 20 mg. A salt of compound (I) and a stable crystalline form of such a salt that has consistent and advantageous physical properties. Furthermore, as an additional independent feature the present invention also provides a formulation making it possible for the pharmacologically active compound (I) to be absorbed to the desired degree In order to prepare pharmaceutical formulations containing compound (I) as the active ingredient for administration to humans there is a need to produce compound (I) in a stable and more soluble form, such as a stable crystalline form, having consistent solid state physical properties which allow pharmaceutical processing. (See lines 1-16.) The salt is tosylate salt of compound 1 which possess vastly improved solid state physical properties and high transient solution and a rapid intrinsic dissolution rate. (See page 4 lines 25-30 bridging page 5, lines 1-2.) Moreover, Alcaraz teaches a method for the treatment of chronic obstructive pulmonary disease (COPD), comprising administering to a patient in need thereof a therapeutically effective amount of compound (I) tosylate. (See lines 22-25 of page 20.) Alcaraz also teaches in general, satisfactory results are obtained when the compounds that include tosylate salt of alvelestat are administered to a human at a daily dosage of between 0.1 mg/kg to 100 mg/kg (measured as the active ingredient). Suitable dose of the compound I can be from 0.5 to 200 mg per day such as 60 mg, 120 mg, and 200 mg per day. The dose of compound (I) may be administered as a single dose or as a divided dose, for example wherein the total daily dose is divided into two or more fractions, which administered during the day. In a particular embodiment the compound (I) tosylate is administered twice a day (BID dosing). (See lines 2-11 of page 30.) For a 60 kg human patient, the 0.1-100 mg/kg equals to 6-6000 mg. The administration can be oral e.g. tablets or capsules. (See 1-10.)
Tov teaches although the use of augmentation therapy restores physiological levels of AAT to patient's plasma, and may protect the remaining structure of lung parenchyma, serious problems in the disease management still remain. There is still uncertainty of the therapy efficacy, and in addition, there is a limited availability of AAT, particularly as the use of intravenous replacement requires relatively large amounts of the protein. Moreover, it does not provide appropriate means for early intervention and prevention of the progression of pulmonary diseases. Early treatment of pulmonary diseases in the absence of severe symptoms may prevent or delay the irreversible damage. There is an unmet need for early intervention and prevention of the progression of pulmonary diseases by using a therapeutically effective amount of alpha-1-antitrypsin (AAT), particularly by administering the AAT via inhalation where the AAT inhalation can be administered as the sole therapy, or in addition to intravenous AAT augmentation therapy. (See lines 30-43 bridging lines 54-60 of column 3.) Tov teaches in the lungs, AAT maintains the damage of the airway and alveoli by directly and stoichiometrically inhibiting the activity of neutrophil elastase. In conditions with lower level of AAT (serum level below the normal range 80 mg/dl), there is access of neutrophil elastase that increases breakdown of elastin leading to the airway destruction. This manifest clinically as chronic obstructive pulmonary disease (COPD) with emphysema and chronic bronchitis. (See lines 34-41 of column 1.) Tov also teaches the pulmonary diseases are selected from the group consisting of alpha 1-antitrypsin deficiency (AATD), small airway disease, chronic bronchitis, emphysema, chronic obstructive pulmonary disease (COPD) with normal level of AAT, cystic fibrosis, bronchiectasis, asthma, pneumonia, parenchymatic and fibrotic lung diseases or disorders, interstitial pulmonary fibrosis and sarcoidosis. (See lines 14-21.) Furthermore, Tov teaches the effective amount of AAT is about 10 mg to about 250 mg AAT per day. (See claim 5.) Furthermore, Tov teaches the AAT may be administered once a week or administration can be repeated at least twice a week, each day or even twice a day. (See lines 10-12 of column 14.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to modify the method taught by NCT03679598 by including the tosylate salt and a subject or patient that has not responded to AAT therapy, and use alvelestat in a minimum total daily dose of 480 mg, 440 mg, and 360 mg to give Applicant’s claimed method. One would have been motivated to do so, because Alcaraz teaches the tosylate salt of alvelestat offers improved pharmaceutical properties such as solubility, and stability compared to the free base form, and also teaches in general, satisfactory results are obtained when the tosylate form of compound I (alvelestat) can be administered to a human at a daily dosage of between 0.1 mg/kg to 100 mg/kg and can be from 0.5 to 200 mg per day such as 60 mg, 120 mg, and 200 mg per day for treating various diseases including COPD where the 0.1-100 mg/kg for a 60 kg human amounts to 6-6000 mg, and lastly because Tov teaches some patients with AATD receiving augmentation therapy can have limited efficacy and limited availability of AAT and also teaches AAT maintains the damage of the airway and alveoli by directly and stoichiometrically inhibiting the activity of neutrophil elastase in the lungs and in conditions with lower level of AAT (serum level below the normal range 80 mg/dl), there is access of neutrophil elastase that increases breakdown of elastin leading to the airway destruction. One would reasonably expect the inhibition of neutrophil elastase with tosylate salt of alvelestat in the amount claimed in claims 11, 18, and 19 in a patient that has not responded to previous AAT therapy to treat COPD with success.
Claims 1, 8, 11, 12, 13, 17, 18, 19, 22, 23-24, and 25-29 are rejected under 35 U.S.C. 103 as being unpatentable over NCT03679598 (National Library of Medicine, Clinical Trial.gov ID, Version 2, 09/22/2018, https://clinicaltrials.gov/study/NCT03679598?tab=history&a=2#version-content-panel) in view of Alcaraz et al (WO2010/094964 A1) and Tov (US10,960,062 B2) as applied to claims 1, 8, 11, 12, 13, 17, 18, 19, 22, and 25-29, in further view of Soy et al (Thorax. 2006 Aug 23;61(12):1059–1064).
The teachings of NCT03679598, Alcaraz, and Tov have been discussed supra.
NCT03679598, Alcaraz, and Tov collectively do not teach the particular dosing regimen recited in claims 23 and 24. However, Alcaraz also teaches in general, satisfactory results are obtained when the compounds that include tosylate salt of alvelestat are administered to a human at a daily dosage of between 0.1 mg/kg to 100 mg/kg (measured as the active ingredient). Suitable dose of the compound I can be from 0.5 to 200 mg per day such as 60 mg, 120 mg, and 200 mg per day. The dose of compound (I) may be administered as a single dose or as a divided dose, for example wherein the total daily dose is divided into two or more fractions, which administered during the day. In a particular embodiment the compound (I) tosylate is administered twice a day (BID dosing). (See lines 2-11 of page 30.) For a 60 kg human patient, the 0.1-100 mg/kg equals to 6-6000 mg. The administration can be oral e.g. tablets or capsules. (See 1-10.)
Soy teaches optimal therapeutic regimen based on population pharmacokinetics for alpha-1-antitrypsin deficiency. It is feasible to extend the interval between doses of AAT to 14 or 21 days to achieve adequate trough total AAT concentrations. This study might be used as a starting point for clinical evaluation of the regimens described. (See Title and Abstract.) Moreover, Soy teaches the individual optimal drug dose and/or interval between doses to reach the recommended threshold of 0.5 g/l total serum AAT can be assessed by Bayesian analysis using a population pharmacokinetic approach can be hypothesized. (See the last paragraph of the left column bridging the first paragraph of the right column.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to optimize the dose schedule taught by NCT03679598 and Alcaraz to administer alvelestat tosylate at a dose of 60 mg twice daily for a first period of time,- administering alvelestat tosylate thereof at a dose of 120 mg twice daily thereafter, wherein the first period is 5-20 days wherein said administration at a dose of 120 mg twice daily is continued for a second period of time, and further comprising:- administering alvelestat tosylate at a dose of 180 mg twice daily for a third period of time, and- administering alvelestat tosylate at a dose of 240 mg twice daily thereafter, wherein said first, second and third periods are 5-20 days, to give Applicant’s claimed method. One would have been motivated to do so via no more than routine optimization, not only because Alcaraz teaches the tosylate salt of alvelestat offers improved pharmaceutical properties such as solubility, and stability compared to the free base form, and also teaches satisfactory results are obtained when the tosylate form of compound I (alvelestat) can be administered to a human at a daily dosage of between 0.1 mg/kg to 100 mg/kg and can be from 0.5 to 200 mg per day such as 60 mg, 120 mg, and 200 mg per day for treating various diseases including COPD where the 0.1-100 mg/kg for a 60 kg human amounts to 6-6000 mg, but also because Soy teaches optimal therapeutic regimen based on population pharmacokinetics for alpha-1-antitrypsin deficiency. It is feasible to extend the interval between doses of AAT to 14 or 21 days to achieve adequate trough total AAT concentrations, where this study might be used as a starting point for clinical evaluation of dosing regimens. One would reasonably expect treatment of COPD to be benefited from the optimization of the dosing regimen taught by NCT03679598, Alcaraz, and Soy.
Conclusion
Claims 1, 8, 11-13, 17-19, and 22-29 are not allowed.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628