DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application is a national stage application under 35 U.S.C. § 371 of International Application No. PCT/EP2020/064444, filed 05/25/2020, which claims the priority benefit of EP Application No. 19176477.8, filed 05/24/2019.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 11/17/2021 was filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Status of the Application
Claims 16, 19, 21, and 23-37 are currently pending and under examination. Claims 16, 19, 21, 23, 25, 27, and 28 been amended. Claims 1-15, 17-18, 20, and 22 have been canceled by applicant without prejudice or disclaimer.
Applicant’s arguments, filed 01/28/2025, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. They constitute the complete set presently being applied to the instant application.
The obviousness rejection below is repeated from the 11/08/2024 Office Action and modified in order to address the most recent amendments.
Claim Rejections - 35 USC § 112
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 16, 19, 21, and 23-37 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 subject infected with gram positive bacteria, does not reasonably provide enablement for prevention of said disease or disorder. 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.
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), the factors to be considered in determining whether a disclosure meets the enablement requirement are as follows:
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 and Breadth of the Claims
Claims 16, 19, 21, and 23-37 are drawn to method of treating a subject infected with gram positive bacteria, the method comprising the step of administering glycylcycline to the subject via inhalation, wherein the glycylcycline is tigecycline, wherein the subject is infected with a mycobacterium of the clade M. abscessus, or a subspecies thereof, wherein the subject is infected with a pulmonary infection. These claims cover diseases that are known to exist and those that may be discovered in the future, for which there is no enablement provided.
The State of the Prior Art and the Predictability or lack thereof in the art
The state of the prior art is that the pharmacological art involves screening in vitro and in
vivo to determine which compounds exhibit the desired pharmacological activities (i.e. what
compounds can treat which specific disease by what mechanism). There is no absolute
predictability even in view of the seemingly high level of skill in the art. The existence of these
obstacles establishes that the contemporary knowledge in the art would prevent one of ordinary
skill in the art from accepting any therapeutic, curative, or preventative regimen on its face.
While a full discussion of each disease which is encompassed by Applicant's claim
language will not be given; the following examples teach that the state of the prior art
with respect to the claimed diseases has not advanced to the point of being predictive of the curative treatment of the breadth of diseases instantly claimed. "Treatment" is defined in the present specification (pgs. 5-6) as follows:
“A glycylcycline for use according to the invention is for use in the treatment of a subject
infected with gram positive bacteria, wherein the glycylcycline is administered by inhalation. In the context of this invention, treatment of a bacterial infection may refer to preventing, ameliorating, curing, and/or delaying an infection with gram positive bacteria. Prevention of an infection may mean that an infection is cured before symptoms of the infection have manifested. Preferably, successful treatment may mean that:
- The severity of at least one symptom of the infection has been reduced, and/or
- A symptom has not manifested while this manifestation could have been expected, and/or
- At least a parameter associated with the infection has been improved.” (Specification pgs. 5-6)
The current state of the art is that that full scope of diseases claimed within instant claims is not curative. The full scope of diseases are not curable or preventable. For example, Boucher et al. (In Vitro Activities of the Glycylcycline GAR-936 against Gram-Positive Bacteria) discloses “The in vitro activities of GAR-936, the 9-t-butylglycylamido derivative of minocycline, were compared with those of doxycycline, minocycline, and tetracycline against 527 gram-positive clinical isolates. GAR-936 inhibited all strains, including those resistant to other tetracyclines, at concentrations of
≤
2 mg/ml, except two strains of JK diphtheroids for which the MIC was 4 mg/ml.” (Abstract).
In contrast, the instant specification does not provide any teaching for treating a JK diphtheroid, a gram positive bacteria as evidenced by Boucher.
The existence of these obstacles establishes that the contemporary knowledge in the art
would prevent one of ordinary skill in the art from accepting any therapeutic, curative, or
preventative regimen on its face.
The Amount of Guidance Present and Presence/Absence of Working Examples
The only guidance disclosed by the specification regarding prevention of a condition
and/or symptom or clinical manifestation associated with systemic infection in a subject is found
on page 2 of the specification with variations found on pages 6-7 and 9.
“In the context of the invention, treating, preventing, curing and/or delaying an infection is preferably assessed or detected after at least one day, two days, three days, four days, one week, two weeks, three weeks, four weeks, one month, two months, three months, four months, five months, six months or more in a treated subject. Treating, preventing, curing and/or delaying an infection is preferably identified in a subject as:
-a prolongation of patient survival of at least one month, several months or more (compared to those not treated or treated with a control or compared with the subject at the onset
of the treatment) and/or
-improvement of the quality of life and observed symptom relief such as pain relief.
In the context of the invention, a patient may survive and/or may be considered as being
disease free. Alternatively, the infection may have been stopped or delayed. In the context of the
invention, an improvement of quality of life and observed pain relief may mean that a patient may need less pain relief drugs than at the onset of the treatment. Alternatively or in combination with the consumption of less pain relief drugs, a patient may be less short of breath than at the onset of the treatment. "Less" in this context may mean 5% less, 10% less, 20% less, 30% less, 40% less, 50% less, 60% less, 70% less, 80% less, 90% less. A patient may no longer need any pain relief drug or respiratory assistance. This improvement of quality of life and observed pain relief may be seen, detected or assessed after at least one week, two weeks, three weeks, four weeks, one month, two months, three months, four months, five months, six months or more of treatment in a patient and compared to the quality of life and observed pain relief at the onset of the treatment of said patient.”
“As a result of treatment, a subject may be cured of all pulmonary infection. In this case it can be said that the lungs of the subject have been sterilised. Preferably at least part of the infecting gram positive bacteria are killed, more preferably all infecting gram positive bacteria are killed.” (sic)
“In preferred embodiments the glycylcycline for use according to the invention is for
preventing infection by gram positive bacteria, preferably by mycobacteria. Such prevention is
preferably in subjects suffering from cystic fibrosis, or in subjects who have recently been cured
from an infection, preferably from a gram positive bacterial infection such as a pulmonary gram
positive bacterial infection, more preferably from a mycobacterial pulmonary infection.” Specification, pg. 9)
The specification does not provide any guidance for determining which particular patient
population would be susceptible to developing a gram positive bacterial infection. Also lacking are data showing that the compounds are capable of treating all or every gram positive bacterial infection. For example, Boucher et al. (In Vitro Activities of the Glycylcycline GAR-936 against Gram-Positive Bacteria) discloses GAR-936 (tigecycline) inhibited all strains, including those resistant to other tetracyclines, at concentrations of <2 mg/ml, except two strains of JK diphtheroids (a gram positive bacteria) for which the MIC was 4 mg/ml, whereas the instant application makes no mention of diphtheroids.
The quantity of experimentation needed, and level of skill in the art
In order to treat every or all gram positive bacterial infection types one would need to precisely identify those subjects with the disease or disorder who are likely to respond to treatment, administer the claimed invention, and demonstrate that administration directly resulted in the subject overcoming the disease or disorder. One skilled in the art would conclude that the guidance in the specification would not have taught one skilled in the art how to treat every or all gram positive bacterial types using the compound of tigecycline, because there is no guidance for how to select a patient population and no evidence that the claimed compound can broadly treat every gram positive bacterial infection type. Given the lack of guidance in the specification and the lack of success in the prior art, one skilled in the art would find that preventing the claimed diseases or disorders would require experimentation that is unduly burdensome.
This rejection may be overcome by amending the claim limitations to a “method of treating not preventing” in the claim preamble.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 16, 19, 21, 23, 25, and 27-34 are rejected under 35 U.S.C. 103 as being unpatentable over Ferro et al. (Tigecycline Is Highly Efficacious against Mycobacterium abscessus Pulmonary Disease) in view of Lee et al. (Tailored Antibiotic Combination Powders for Inhaled Rotational Antibiotic Therapy).
The instant claims are directed to a method of treating a subject infected with gram positive bacteria, the method comprising the step of administering glycylcycline to the subject via inhalation, wherein the glycylcycline is tigecycline, and wherein the subject is infected with a mycobacterium of the clade M. abscessus, or a subspecies thereof, wherein the subject is infected with a pulmonary infection.
Ferro et al. teaches tigecycline is the first developed glycylcycline designed to overcome mechanisms of resistance that are known for older tetracyclines and demonstrated broad in vitro effects on several Gram-positive and Gram-negative bacteria as well as being FDA approved for treatment of community acquired bacterial pneumonia (pg.. 2895, left col., 1st para.). Ferro disclosed the test strain of M. abscessus subsp. abscessus ATCC 19977 (American Type Culture Collection, Manassas, VA) in the materials and methods section and that Mycobacterium abscessus causes chronic pulmonary infections that are extremely difficult to cure. (Abstract and pg. 2895, materials and methods, 1st para.). Ferro also teaches tigecycline is efficacious against the notoriously resistant M. abscessus and that it exhibited a considerable microbial kill below the stasis line, exceeding what has been previously observed for amikacin or moxifloxacin and could be the first truly bactericidal drug for M. abscessus (Discussion, pg. 2898, 1st para). Ferro also discloses a 200-mg/day dose achieved a 1-log kill target exposure in close to 90% of patients and that this large dose will be administered together with an antiemetic agent, during the first few months of therapy in a multidrug regimen to rapidly drive down bacterial burden (pg. 2899, left col., 2nd para.). Ferro discloses a tigecycline dose range of 50-200 mg/day (fig. 6, pg. 2899).
However, Ferro et al. fail to disclose a dry powder inhalation method of administration of the pharmaceutical compound of tigecycline.
Lee et al. teaches a method of treating a subject infected with gram-negative bacteria in which the method of treatment comprises a step of administering glycylcycline to a subject via dry powder inhalation (Page 1502, Col., 1 ). Lee discloses tigecycline (TIG) in a spray-dried powder formulation with a pharmaceutically acceptable excipient, colistin (COL) on table 4, pg., 1507 wherein the inhalable formulation consists of colistin/tigecycline/rifampicin listed as [COL/TIG/RIF], wherein the microparticles have a volume diameter of 1.4 +/- 0.1 μm (Page 1507, Table 4). Lee teaches the description of the positives surrounding a dry power inhalation are mentioned as, "[e]levated drug concentrations can be achieved locally at the site of lung infection without the adverse effects of systemic toxicity A dry powder inhaler (DPI) formulation is superior over the other aerosol delivery modes (e.g., nebulizer or metered dose inhaler) in terms of stability, delivery efficiency, portability, ease-of-use, and the avoidance of undesired precipitation in solutions," (Page 1502, left col., 2nd para.). Lee also discloses in the In Vitro Aerosol Performance section, “The aerosolization performance results of the single and ternary spray-dried formulations are shown in Figure 5 and Table 7. In this work, airflow of 60 L/min was used to simulate the reduced inspiratory effort achieved by patients with compromised lung functions (e.g., pneumonia and cystic fibrosis” (In Vitro Aerosol Performance, pg. 1508, 1st para.).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the instant application, to combine Ferro’s teachings of treating a gram positive bacterial infection of M. abscessus subspecies abscessus and pneumonia with 50-200mg/day dose of tigecycline in a multi-drug regimen with Lee’s disclosures of a dry powder inhaler (DPI) of tigecycline able to produce microparticles having a volume diameter lower than 10 μm with an excipient of colistin to a patient with pneumonia or cystic fibrosis because Lee’s disclosure of delivering elevated drug concentrations locally at the site of lung infection with a dry powder inhaler would contribute the advantageous attributes of avoiding adverse systemic toxicity or precipitation in solution and improve stability, delivery efficiency, portability, ease-of-use of the pharmaceutical composition and solve Ferro’s use of an additional antiemetic and improve tolerability of the treatment in patients. See MPEP 2131.03, MPEP 2144.05(II) and MPEP 2144.06.
A person of ordinary skill in the art would have been motivated to administer a dry powder inhaler form of a pharmaceutical composition of 50-200 mg/day tigecycline and excipients to a patient suffering from M. abscessus subspecies abscessus, pneumonia or cystic fibrosis because the tigecycline dry powder delivery teachings of Lee would have improved Ferro’s disclosures of treating the gram positive bacteria M. abscessus subspecies abscessus with tigecycline. Therefore, a skill artisan would have had a reasonable expectation of success in treating M. abscessus subspecies abscessus, pneumonia or cystic fibrosis with tigecycline.
Response to Arguments
Applicant’s arguments, see pages 5-8, filed 01/28/2025, with respect to the rejection(s) of claim(s) 16-19 and 21-22, 25-29 under 35 U.S.C. §103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Ferro et al. (Tigecycline Is Highly Efficacious against Mycobacterium abscessus Pulmonary Disease) in view of Lee et al. (Tailored Antibiotic Combination Powders for Inhaled Rotational Antibiotic Therapy).
The combination of Ferro and Lee address the newly amended instant claim limitations.
Conclusion
All claims are rejected, no claims are allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNESTO VALLE JR whose telephone number is (703)756-5356. The examiner can normally be reached 0730-1700 M-F EST, 1st Friday off.
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/E.V./Examiner, Art Unit 1623
/SAMANTHA L SHTERENGARTS/Primary Examiner, Art Unit 1623
