DETAILED ACTION
This office action is in response to applicant’s filing dated March 9, 2026.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 9, 2026 has been entered.
Status of Claims
Claims 34 and 54-73 are pending in the instant application. Acknowledgement is made of Applicant's amendments filed March 9, 2026. Acknowledgement is made of Applicant's cancelation of claims 1-33 and 35-53; and addition of new claims 54-73.
Priority
The present application is a 371 of PCT/EP2021/025140, filed April 16, 2021, which claims the benefit of US Provisional Application 63/011,474, filed April 17, 2020 and claims benefit of foreign priority to EP 20170072.1 and EP 20183292.0 filed April 17, 2020 and June 30, 2020, respectively.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on March 9, 2026 and March 31, 2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner, except where marked with a strikethrough.
Claim Rejections - 35 USC § 112(b)
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.
Claim 34 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 34 recites: Lefamulin in the form of an acid addition salt with itaconic acid, optionally lefamulin itaconate.
By broadest reasonable interpretation, the phrase “lefamulin in the form of an acid addition salt with itaconic acid” is lefamulin itaconate. It is unclear what other lefamulin acid addition salts are encompassed by the phrase “lefamulin in the form of an acid addition salt with itaconic acid” if lefamulin itaconate is optional.
Claim Rejections - 35 USC § 112(a)
Scope of Enablement
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 56-53 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 a method of treating community-acquired bacterial pneumonia and viral infections caused by measles virus, respiratory syncytial virus, influenza virus, dengue virus, zika virus, or rhinovirus comprising administering lefamulin, does not reasonably provide enablement for a method for treating or preventing any inflammatory disease characterized by neutrophilic inflammation. 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 rejection.
To be enabling, the specification of the patent application 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 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
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 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). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 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:
1. The nature of the invention, state and predictability of the art, and relative skill of those in the art
The invention relates to a method treating or preventing any inflammatory disease characterized by neutrophilic inflammation.
The relative skill of those in the art is high, generally that of a D.V.M. or Ph.D. The artisan using Applicant’s invention would generally be a veterinarian with a V.M.D. degree and several years of experience.
The factor is outweighed, however, by the unpredictable nature of the art. It is well established that “the scope of enablement varies with the degree of unpredictability of the factors involved” and physiological activity is considered to be an unpredictable factor. See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved); Nationwide Chemical Corporation, et. al. v. Wright, et. al., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances); Ex parte Sudilovsky 21 USPQ2d 1702 (Applicant’s invention concerns pharmaceutical activity. Because there is no evidence of record of analogous activity for similar compounds, the art is relatively unpredictable); In re Wright 27 USPQ2d 1510 (the physiological activity of RNA viruses was sufficiently unpredictable that success in developing specific avian vaccine was uncertain). As illustrative of the state of the art, the examiner cites Nemeth et al (Nat Rev Drug Discov, 2020; 19:253–275, published January 22, 2020).
Nemeth, cited for evidentiary purposes, teaches neutrophils are the most abundant circulating leukocytes, being the first line of defence against bacterial and fungal infections; however, neutrophils also contribute to tissue damage during various autoimmune and inflammatory diseases, and play important roles in cancer progression; the intimate but complex involvement of neutrophils in various diseases makes them exciting targets for therapeutic intervention but also necessitates differentiation of beneficial responses from potentially detrimental side effects; a variety of approaches to therapeutically target neutrophils have emerged, including strategies to enhance, inhibit or restore neutrophil function, with several agents entering clinical trials; however, challenges and controversies in the field remain (abstract).
Nemeth teaches neutrophils play diverse roles in various infectious and inflammatory diseases, making them a potentially attractive target for therapeutic intervention; however, several aspects (such as the similarity of neutrophils to other myeloid cells or the potential risk of developing severe infections) have limited prior interest in targeting neutrophils; there are also a number of uncertainties and controversies related to various aspects of neutrophils, including their lifespan, transcriptional activity and roles in cancer and the potential existence of neutrophil subpopulations; in addition, neutrophils may even escape therapeutic interventions due to their exceptional turnover and unexpected plasticity, particularly in cancer (page 270, right, 4th paragraph).
This article plainly demonstrates that the art of developing and testing drugs, particularly for use in treating any inflammatory disease characterized by neutrophilic inflammation, is extremely unpredictable.
2. The breadth of the claims
Claims 56-73, while narrow in terms of the compounds administered, are very broad in terms of the type of diseases being treated: all types of inflammatory diseases characterized by neutrophilic inflammation.
3. The amount of direction or guidance provided and the presence or absence of working examples
The specification provides examples wherein Lefamulin was administered in cells inoculated with a measles virus (Example 11); respiratory syncytial virus (Examples 9 and 10); influenza virus (example 15); dengue or zika virus (Example 13); and a rhinovirus (Example 14). However, the specification does not provide any data that shows that lefamulin is useful for treating any inflammatory disease characterized by neutrophilic inflammation other than viral infections caused by measles virus, respiratory syncytial virus, influenza virus, dengue virus, zika virus, or rhinovirus. Moreover, the specification does not provide any data that shows that lefamulin is useful for preventing any inflammatory disease characterized by neutrophilic inflammation.
4. The quantity of experimentation necessary
Because of the known unpredictability of the art (as discussed supra) and in the absence of experimental evidence commensurate in scope with the claims, the skilled artisan would not accept that lefamulin could be predictably used as prevention or treatment for all inflammatory disease characterized by neutrophilic inflammation other than community-acquired based pneumonia and viral infections caused by measles virus, respiratory syncytial virus, influenza virus, dengue virus, zika virus, or rhinovirus comprising administering lefamulin.
Determining if a particular diet will treat any particular disease state would require formulation into a dosage form, and subjecting into clinical trials or to testing in an assay known to correlate to clinical efficacy of such treatment. This is undue experimentation given the limited guidance and direction provided by Applicants.
Accordingly, the inventions of claims 56-73 do not comply with the scope of enablement requirement of 35 U.S.C 112, first paragraph, since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation with no assurance of success.
Response to Arguments
Since a new rejection was issued (see above), it is the Examiner’s belief that most of the arguments presented by Applicant have been considered/answered in the rejection itself.
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 54, 56-59, 62, 63, 65-68, 71, and 72 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Alexander et al (JAMA, 2019; 322(17):1661-1671, cited in the IDS dated April 28, 2023).
Regarding claims 56 and 65, Alexander teaches lefamulin is the first pleuromutilin antibiotic approved for intravenous and oral use in humans (page 1662, left, 3rd paragraph); a phase 3, double-blind, double-dummy, parallel-group randomized clinical trial was designed to evaluate lefamulin treatment over 5 days (minimum treatment duration recommended by CABP (community-acquired bacterial pneumonia). CABP reads on an inflammatory disease characterized by neutrophilic inflammation in view of Reine et al (BMC Research Notes, 2020; 13(1):203 pp 1-5, published April 8, 2020), which teaches neutrophil dysfunction is well recognized in patients with CAP (community-acquired pneumonia). Thus, Alexander teaches a method of treating an inflammatory disease characterized by neutrophilic inflammation, community-acquired bacterial pneumonia, comprising administering lefamulin.
Regarding claims 57, 58, 66, and 67, the wherein limitations of these claims, are considered to simply express the intended result of a process step positively recited, which is not given patentable weight (See MPEP 2111.04: [T]he court noted (quoting Minton v. Nat'lAss'n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQgd 1614, 1690 (Fed. Cir. 2003)) that a "'whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.'" Hoffer v. Microsoft Corp., 405 F.3d 1396, 1399, 74 USPQgd 1481, 1483 (Fed. Cir. 2005).).
In the instant case, the wherein clause is directed to the intended result (i.e. reduces the levels of proinflammatory cytokines, chemokines, or metalloproteinases, TNF-α,IL-6, IL-1β, GM-CSF, CXCL1, CXCL2, CCL2, or MMP-9) of the process step positively recited (i.e. administering lefamulin).
Regarding claims 59 and 68, Alexander teaches comorbidities of the subjects treated included chronic obstructive pulmonary disease (COPD) and asthma. Thus, Alexander teaches a method of treating an inflammatory disease characterized by neutrophilic inflammation, community-acquired bacterial pneumonia, comprising administering lefamulin, in a subject suffering from CABP and COPD or asthma.
Regarding claims 54, 62, 63, 71, and 72, Alexander teaches patients received oral lefamulin (600mg every 12 hours for 5 days; n = 370) (abstract).
Claims 54 and 55 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Xenleta™ (Highlights of prescribing information, Nabriva Therapeutics US, Inc., 2019).
Xenleta™ teaches XENLETA, a pleuromutilin derivative, is available as 14-O-{[(1R,2R,4R)-4-amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin in the form of an acetic acid salt (acetate) (page 12, 11 Description) and XENLETA Tablets; blue, oval, film-coated tablet with ‘LEF 600’ printed in black on one side; each tablet contains 600 mg of lefamulin (page 21).
Thus, Xenleta™ anticipates the composition of claims 54 and 55.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 61, 64, 70, and 73 are rejected under 35 U.S.C. 103 as being unpatentable over Alexander et al (JAMA, 2019; 322(17):1661-1671, cited in the IDS dated April 28, 2023) as applied to claims 56-59, 62, 63, 65-68, 71, and 72 above, and further in view of Xenleta™ (Highlights of prescribing information, Nabriva Therapeutics US, Inc., 2019).
Alexander teaches all the limitations of claims 61, 64, 70, and 73 (see above 102), except wherein the oral lefamulin is in the form of a tablet or Lefamulin is administered by injection.
However, Xenleta™ teaches XENLETA is a pleuromutilin antibacterial indicated for the treatment of adults with community-acquired bacterial pneumonia (CABP) caused by susceptible microorganisms; XENLETA (lefamulin) injection, for intravenous use; and XENLETA (lefamulin) tablets, for oral use (page 1, left).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to administer the oral Lefamulin composition in the method of Alexander in the form of a tablet since the prior art teaches that oral tablet formulations comprising Lefamulin are commercially available and FDA approved for treating CABP. Similarly, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to modify the method taught by Alexander to administer the Lefamulin by injection since the prior art teaches that formulations formulated for injection comprising Lefamulin are commercially available and FDA approved for treating CABP.
Taken together, all this would result in the practice of the method of claims 61, 64, 70, and 73 with a reasonable expectation of success.
Claims 60 and 69 are rejected under 35 U.S.C. 103 as being unpatentable over Alexander et al (JAMA, 2019; 322(17):1661-1671, cited in the IDS dated April 28, 2023) as applied to claims 56-59, 62, 63, 65-68, 71, and 72 above, and further in view of Mang et al (WO 2008/113089 A1, cited in the IDS dated April 28, 2023).
Alexander teaches all the limitations of claims 60 and 69 (see above 102). Alexander further teaches common causative pathogens of community-acquired bacterial pneumonia (CABP) include Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, and the atypical pathogens Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila (page 1662, left, 1st paragraph).
Alexander does not teach wherein the lefamulin is administered by inhalation.
However, Mang teaches pleuromutilin derivatives for the treatment of diseases mediated by microbes (Title); pleuromutilin derivatives of formula (I) (Abstract); and the compounds of the present invention show antimicrobial, e.g. antibacterial, activity against gram positive bacteria, such Staphylococcus aureus, Streptococcus pneumoniae, Moraxella catarrhalis, Haemophilus influenzae, and Legionella pneumophila (page 9, 4th paragraph). Moreover, Mang teaches a compound of formula (I) is 14-O-{[(1R, 2R, 4R)-4-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin (claim 7) and the compounds of the invention may be administered by any conventional route including oral, and in form of injectable solutions or suspensions and inhaler powder (page 11, 2nd paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to modify the method taught by Alexander to administer the Lefamulin by inhalation since the prior art teaches that lefamulin can be alternatively formulated for oral administration, for injection, and/or inhalation.
Taken together, all this would result in the method of claims 60 and 69 with a reasonable expectation of success.
Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over Mang et al (WO 2008/113089 A1, cited in the IDS dated April 28, 2023) as applied to claims 56-59, 62, 63, 65-68, 71, and 72 above, and further in view of Brown et al (US 2007/0167495 A1).
Regarding claim 34, Mang teaches pleuromutilin is a naturally occurring antibiotic (page 1, 1st paragraph). Mang teaches pleuromutilin derivatives for the treatment of diseases mediated by microbes (Title); pleuromutilin derivatives of formula (I) (Abstract); and the compounds of the present invention show antimicrobial, e.g. antibacterial, activity against gram positive bacteria, such Staphylococcus aureus, Streptococcus pneumoniae, Moraxella catarrhalis, Haemophilus influenzae, and Legionella pneumophila (page 9, 4th paragraph). Moreover, Mang teaches a compound of formula (I) is 14-O-{[(1R, 2R, 4R)-4-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin (claim 7) in the form of a salt (claim 8) and the compounds of the invention may be administered by any conventional route including oral, and in form of injectable solutions or suspensions and inhaler powder (page 11, 2nd paragraph). 14-O-{[(1R, 2R, 4R)-4-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin reads on lefamulin.
Mang does not teach the lefamulin salt is lefamulin itaconate.
However, Brown teaches pleuromutilin compounds of the formula (IA) (abstract):
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Brown further teaches the compounds of the present invention and their pharmaceutically acceptable salts or derivatives may be used for the treatment of infections caused by, for example, Staphylococcus aureus, Streptococcus pneumoniae, Moraxella catarrhalis, Haemophilus sp., and Legionella sp. [0101]. Moreover, Brown teaches the compounds of the invention may be in the form of an acid-addition salt [0053]; and pharmaceutically acceptable acid-addition salts include itaconate [0054].
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to formulate a itaconate salt of lefamulin with a reasonable expectation of success, since the prior art teaches structurally similar pleuromutilin derivatives taught for the same purpose can be formulated as itaconate salt.
Taken together, all this would result in the composition of claim 34 with a reasonable expectation of success.
Conclusion
Claims 34 and 54-73 are rejected.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RAYNA B RODRIGUEZ whose telephone number is (571)272-7088. The examiner can normally be reached 8am-5:00pm, Monday - Thursday.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached at 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Rayna Rodriguez/ Primary Examiner, Art Unit 1628
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