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 .
Claim Status
Claims 1-5, 7-12, 16-19, and 21-22 are pending following the Reply filed 10/21/2025. Claim 12 has been amended without introducing new matter, and claims 14 and 15 have been cancelled. Claims 1-5, 7-12, 16-19, and 21-22 have been examined on the merits.
Notice
Errors are noted in the amended claim set filed 10/21/2025. The phrase “susceptible to having the acute lung injury” in claim 12 was annotated in the previous claim listing (filed 07/16/2025) as being added to the claim (i.e., the phrase is underlined). However, in the present claim set (filed 10/21/2025), “susceptible to having an acute lung injury” is underlined, while the only actual change made to this recitation was “the” to “an” (“an”). In other words, the complete phrase should not be underlined, and the word “the” should have been annotated by strike-through instead of deleted. In addition, claim 21 contains the annotated phrase “a” on line 10, which is an amendment carried over from the previous claim set. As claim 21’s status identifier (“previously presented”) is correct, claim 21 should not show any annotations.
Per MPEP 714(II)(B), “[a]ll claims being currently amended must be presented with markings to indicate the changes that have been made relative to the immediate prior version” (Emphasis added). Applicant is hereby reminded that the status of all claims in the application must be given with the appropriate status identifier and must only include markings to show the changes that have been made relative to the immediate prior version.
As no other errors were noted in the currently amended claim set, examination of the claims has proceeded on the merits.
Sequence compliance
Examiner acknowledges Applicant’s filing of an amendment to the specification on 10/21/2025 to address the sequence compliance issues raised in the previous Office Action. However, the amendment does not address the covered sequence of “(HEXXHXXGXXH)” on pg. 17, line 22 (see specification filed 08/02/2022). Note that the covered sequence contains four or more specifically defined amino acid residues (i.e., H, E, H, G, H). Each covered sequence that meets the minimum length threshold must have its “SEQ ID NO:” next to each occurrence within the disclosure (i.e., SEQ ID NO: X). See CFR §§ 1.821 -1.825 and MPEP § 2422. The following are required for applicable sequence listings:
A sequence listing text file (in .txt format) is always required under 37 CFR 1.821(e). The computer readable file (also referred to as a “CRF”) is not an official part of the application unless it is incorporated by reference.
An “official copy” that forms part of the application is also required under 37 CFR 1.821(c). The requirement for an “official” copy can be fulfilled in several ways (see MPEP 2422.03):
incorporation by reference of the CRF copy (preferred)
pdf copy filed via EFSWeb
paper copy filed via mail
Rule 52 copy filed on a CD (rare, and mostly used for large sequence listings that cannot be filed via EFSWeb)
The incorporation by reference must include the name of the file, the size in bytes, and the create date.
Each covered sequence that meets the minimum length threshold must have its “SEQ ID NO:” next to each occurrence within the disclosure, i.e. SEQ ID NO: X.
Appropriate correction is required.
Maintained Rejections and New Rejections Necessitated by Amendment
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 12 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention.
The term “susceptible” in claim 12 is a relative term which renders the claim indefinite. The term “susceptible” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In this case, a person of ordinary skill would not be apprised as to which patients are “susceptible to having an acute lung injury” and which patients are not. On one hand, one may interpret the limitation as including any patient having lungs, because any patient having lungs is “susceptible” to having an acute lung injury. Conversely, this limitation could be interpreted as including patients which are more susceptible than other patients, while excluding those other patients. However, there is no standard set forth in the specification for ascertaining what requisite degree of “susceptibility” would satisfy this limitation. Any patient who is more susceptible to an acute lung injury when compared to another patient may also be less susceptible when compared to yet another patient. As the claim does not distinctly identify which patients are included or excluded from the claimed limitation, the metes and bounds of the claimed method have not been clearly set forth. See MPEP 2173.05(b).
Suggestion to obviate the rejection: Applicant may, for example, remove the phrase “susceptible to” on line 2, so the claim recites, “in a patient having an acute lung injury”.
Claim Rejections - 35 USC § 112(a) – 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 12 and 16-19 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 preventing ARDS and/or pulmonary fibrosis in a patient having an acute lung injury, does not reasonably provide enablement for preventing ARDS in any patient. 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 and use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure would require undue experimentation include: A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims – The standard under 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. In addition, when analyzing the scope of enablement, the claims are analyzed with respect to the teachings of the specification and are to be “given their broadest reasonable interpretation consistent with the specification.” See MPEP 2111 [R-5]; Phillips v. AWH Corp., 415 F.3d 1303, 75 USPQ2d 1321 (Fed. Cir. 2005); and In re Hyatt, 211 F.3d 1367, 1372, 54 USPQ2d 1664, 1667 (Fed. Cir. 2000). Applicant always has the opportunity to amend the claims during prosecution, and broad interpretation by the examiner reduces the possibility that the claim, once issued, will be interpreted more broadly than is justified. In re Prater, 415 F.2d 1393, 1404-05, 162 USPQ 541, 550- 51 (CCPA 1969).
As discussed under 35 U.S.C. 112(b), “a patient susceptible to having an acute lung injury” is broadly interpreted as including any patient having lungs, because this patient population (patients that are “susceptible”) has not been clearly defined in the claim. As such, the broadest reasonable interpretation of independent claim 12 is a method of preventing ARDS and/or pulmonary fibrosis in any patient having lungs, including those without any signs or symptoms of an acute lung injury or any particular risk factor for developing ARDS. This is also because the phrase “acute lung injury” is interpreted to include any injury to the lungs, including traumatic injuries, which reasonably any patient may be “susceptible” to. This interpretation of “an acute lung injury” is further supported in the claims with the recitation of “wherein the acute lung injury is the result of… trauma to the lung tissue” as recited in claim 4.
Further, in light of the specification (discussed further below), the BRI of the claims may also include preventing an acute lung injury in order to prevent ARDS. Hence, the claims appear to read on a significant number of inoperative embodiments (e.g., the treatment and/or prevention of infectious pneumonia, an occupational exposure, or lung cancer to prevent ARDS), while the specification does not clearly identify which embodiments are operative, requiring undue experimentation to determine those that are operative. Hence, a skilled artisan would not know how to use the method with a reasonable expectation of success for this scope, based solely on what is disclosed in the specification.
The amount of direction provided by the inventor – Regarding prevention, the specification states, “[p]reventing a condition or disorder involves administering a formulation comprising aerosolized collagenase to a patient prior to onset of the condition” (see pg. 40, lines 12-14; Emphasis added). The specification further states, “ARDS is typically provoked by an acute injury to the lungs, such as sepsis, pancreatitis, trauma, pneumonia, aspiration, as well as COVID- related illnesses” (see pg. 9, lines 10-12). The specification also states that “in some embodiments, the acute lung injury is selected from COPD, lung cancer, asthma, cystic fibrosis, emphysema, bronchitis, bronchiectasis, interstitial lung disease, interstitial fibrosis, bacterial pneumonia, viral pneumonia, fungal pneumonia, parasitic pneumonia, mycobacteria-caused pneumonia, occupational lung diseases, systemic lupus erythematosus, rheumatoid arthritis, scleroderma, dermatomyositis, mixed connective tissue disorder, vasculitis associated lung disease, sarcoid, or combinations thereof” (see pg. 2, para. 5 to pg. 3, para. 1).
However, the specification does not discuss how to identify patients who are “susceptible” to having one of the above conditions or how administering collagenases before the onset of these conditions would be expected to prevent ARDS. Further, the underlying mechanisms described in the disclosure appear to affect the lungs in a manner that would require the injury/disease to be present. The specification states that the invention “is aimed at reducing the excessive collagen deposition associated with ARDS secondary to local deficiency in native MMP at the alveolar lung surface interphase level” and “nebulized Ccol [a type of collagenase] will reduce excessive ECM deposition” (see pg. 2, lines 5-8). Hence, if the administration of collagenases reduces the excessive collagen depositions seen in ARDS and other lung conditions, there remains an open question as to how such administrations would impact lungs that have not (yet) been impacted by such excessive collagen depositions.
The specification further states that a “critical contrast” between Ccol and MMPs (which are another type of collagenase), is that Ccol is relatively incapable of digesting or harming native viable human collagen and poses no threat to endothelial cells (see pg. 31, lines 14-15, 23-24). “In contrast native MMPs, like MMP-1 for example, are only able to degrade native collagen structures and therefore not only cause initial inflammatory insults but also limits their ability to digest fibrotic denatured collagen scaffolds” (see pg. 31, lines 27-29; Emphasis added). Note that the administration of native MMPs, including MMP-1, are within the scope of the claims (e.g., in view of dependent claim 17). Hence, there is a reasonable doubt that administering such collagenases to healthy lung tissue would be preventative, particularly when the onset of ARDS is associated with excessive collagen deposition and inflammatory conditions in the lungs, and the collagenases of the claims are known to cause inflammatory insults.
State of the prior art / Level of predictability in the art – There are no teachings in the prior art to even suggest that the administration of collagenases to the lungs would be able to prevent any and all conditions that lie within the scope of “an acute lung injury”, such as infectious pneumonia, lung cancer, or occupational exposures, which are recited in the claims as being included in this scope. Further, there are few teachings in the prior art of record regarding any successful method to prevent ARDS.
In view of Carney et al. (cited on Form 892), previous strategies to prevent acute lung injury and ARDS include inhibiting the release of MMPs from neutrophils, which damage alveolar-capillary basement membranes and the extracellular matrix, resulting in acute lung injury clinically defiant as adult respiratory distress syndrome (ARDS) (see Abstract). Hence, previous strategies to prevent these conditions include inhibiting MMPs, as opposed to administering them.
Thus, there exists a lack of predictability in the prior art when preventing ARDS and other acute lung injuries, and even more so when attempting to do so by the administering of collagenases to the lungs. In deciding In re Fisher, 166 USPQ 18, 24 (CCPA 1970), the Court indicated the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. “Tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” Genentech Inc. v. Novo Nordisk A/S, 42 USPQ2d 1001, 1005 (CA FC 1997).
In the instant case, even if the guidance provided in Applicant’s disclosure is sufficient to overcome some of the unpredictability in the art, e.g., for a method of preventing ARDS in a patient having an acute lung injury, a person of ordinary skill could not use this same guidance to prevent ARDS in any patient with a reasonable expectation of success and without undue experimentation.
The existence of working examples – When considering the factors relating to a determination of non-enablement, if all the other factors point toward enablement, then the absence of working examples will not by itself render the invention non-enabled. In other words, lack of working examples or lack of evidence that the claimed invention works as described should never be the sole reason for rejecting the claimed invention on the grounds of lack of enablement (see MPEP 2164.02(I)). However, lack of a working example is a factor to be considered, especially in a case involving an unpredictable and undeveloped art.
In the instant case, no working examples are present in the specification which can be relied upon to overcome the other factors used to determine undue experimentation. Furthermore, Applicant’s prophetic examples (see pgs. 43-59) do not disclose any predictions regarding the prevention of ARDS when using the claimed method.
Conclusion – The amount of guidance, direction, and exemplification disclosed in the specification, as filed, would not have been sufficient to have enabled the skilled artisan to make and/or use the claimed invention at the time the application was filed without undue and/or unreasonable experimentation. As discussed above, one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed methods for preventing ARDs in any patient without first making a substantial inventive contribution. Furthermore, the claims read on a significant number of inoperative embodiments, while the specification does not clearly identify those that are operative, which requires undue experimentation to determine those that are operative.
What Applicant has shown is a starting point from which, when given the bid to do so by the instant claims, someone else skilled in the art may pick up a path of studies that may lead to the completion of the claimed invention. However, it is not sufficient for the specification to provide merely “a starting point, a direction for further research”; it must provide “reasonable detail” sufficient to enable a person of ordinary skill in the art to make or use the invention. Automotive Technologies Intern., Inc. v. BMW of North America, Inc., 501 F.3d 1274, 1284 (Fed. Cir. 2007) (Emphasis added).
“Enabling the full scope of each claim is part of the quid pro quo of the patent bargain. A patentee who chooses broad claim language must make sure the broad claims are fully enabled. The scope of the claims must be less than or equal to the scope of the enablement to ensure that the public knowledge is enriched by the patent specification to a degree at least commensurate with the scope of the claims.” Sitrick v. Dreamworks, LLC, 516 F.3d 993, 999 (Fed. Cir. 2008) (Emphasis added).
In conclusion, upon careful consideration of the factors used to determine whether undue experimentation is required, in accordance with the Federal Circuit decision of In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988), the amount of guidance, direction, and exemplification disclosed in the specification, as filed, is not deemed sufficient to have enabled the skilled artisan to make and/or use the full scope of the claimed invention at the time the application was filed without undue and/or unreasonable experimentation.
Therefore, claims 12 and 16-19 are rejected under 35 U.S.C. 112, first paragraph, for failing to meet the enablement requirement.
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, 4-5, 8, 10-11 and 21-22 are rejected under 35 U.S.C 103 as being unpatentable over Faudoa, US 20070003541 A1 (previously cited).
Regarding claim 1, Faudoa discloses, “a method of treating wounds by administering…to an individual, e.g., a human, suffering from a wound an effective amount of collagenase. In some embodiments, the collagenase includes a MMP, e.g., MMP-1” (see pg. 2, para. [0007]). Faudoa states that “A ‘wound,’ as used herein, includes injuries to the skin or other epithelium and, in some cases, subcutaneous tissue, initiated in any way… Non-exclusive examples of wounds include… poorly healing wounds… normal surgical invasions, traumatic wounds… airway/lung lesions… other internal wounds” (see pg. 20, para. [0199]). The broadest reasonable interpretation of “an acute lung injury” is any injury to the lungs. Hence, an “airway/lung lesion” satisfies the limitation of an “acute lung injury”.
Faudoa states that “In terms of treatment, an ‘effective amount’ of a composition of the invention is an amount that is sufficient to palliate, ameliorate, stabilize, reverse or slow the progression of a wound or other condition… Such amounts are readily ascertained by one of ordinary skill in the art” (see pg. 20, para. [0202]). Faudoa further discloses, “[d]irect delivery of the compositions will generally be accomplished by oral and pulmonary administration…and may be directed towards any tissue exhibiting a wound…Administration of the therapeutic combinations of the invention can be accomplished by…aerosol spray…with an appropriate formulation of the selected composition made up of a combination of the therapeutics appropriate for a particular treatment” (see pg. 21-22, para. [0215]). Faudoa’s disclosure of “direct delivery” by “pulmonary administration” meets the limitation of “administered to the lungs at a site of a proximate acute injury”, and Faudoa’s disclosure of “aerosol spray” meets the limitation of “aerosolized collagenases”.
Faudoa does not explicitly recite, “wherein the one or more collagenases are administered at a dose of about 10-300 U/kg of the patient’s body weight”.
Faudoa teaches that an “effective amount” is an amount that is sufficient to palliate, ameliorate, stabilize, reverse or slow the progression of a wound or other condition, further stating, “[s]uch amounts are readily ascertained by one of ordinary skill in the art” (see pg. 20, para. [0202]) and “[a]mounts and concentrations of each agent are known in the art and the appropriate dosage may be found by no more than routine experimentation” (see pg. 22, para. [0218]).
Faudoa teaches that for “the administration of collagenase, for example, MMP-1, the dosage can be in the range of about 5 μg to about 50 mg/kg of tissue to which the application is directed” (see pg. 29, para. [0300]). Faudoa also teaches the collagenase may have an activity of greater than 50 U/mg (see pg. 3, para. [0027]). For example, if one were to apply Faudoa’s teachings in a patient having 1.0 kg of lung tissue, at a dose of 5 μg to 50 mg/kg of tissue, and an enzyme activity of 50 U/mg, a person of skill may arrive at an enzyme activity of 0.25-2,500 U. In a patient weighing 62 kg, this would equate to about 0.004-40 U/kg of body weight, which overlaps with the claimed range of 10-300 U/kg of body weight. Hence, a person of skill would have reasonably arrived at doses in U/kg that fall within the claimed parameter.
Therefore, a person having ordinary skill in the art would have been able to use the reference range to arrive at dosages that are within the claimed range through no more than routine optimization . This is because Faudoa provides a result-effective variable as a starting point in mg/kg of tissue for a person of ordinary skill to have routinely optimized to arrive at the claimed range in U/kg of patient body weight. It was also well within the ordinary skill in the art to have determined, if necessary, the activity of the enzyme (i.e., “U”) and to have correlated kg of tissue to kg of body weight. Moreover, the instant specification does not disclose any evidence for the criticality of the claimed range of “10-300 U/kg”. See MPEP 2143 (II) which states that, “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.” Hence, in the absence of any unexpected results to show that the claimed range was critical, it would have been obvious for one to have adapted the ranges taught by Faudoa to have arrived at an effective dosage within the claimed range for use with a similar pulmonary aerosol for treating a lung lesion (“acute lung injury”) in a patient.
Regarding claim 4, the instant claim is obvious for the same reasons as claim 1 and in light of Faudoa’s teaching that, “[t]he compositions and methods of the invention are also useful in enhancing the repair of tissue damage, e.g., traumatic…wherein the repair and/or regeneration of tissue defects or damage is desired.” (Paragraph 0192). A method of treating traumatic internal wounds to the epithelium of the lungs, i.e., lung lesions, meets the limitation of, “wherein the acute lung injury is the result of trauma to the lung tissue”. Hence, it would have been obvious to have used the method taught by Faudoa to treat an acute lung injury that is the result of “trauma to the lung tissue”.
Regarding claim 5, as discussed above for claim 1, Faudoa teaches a method for treating a lung injury by administering a therapeutic combination of an aerosol spray via oral and pulmonary administration, as discussed above. As the prior art composition is an aerosol administered via the oral route, it would have been obvious to have administered the aerosol spray by oral inhalation.
Regarding claim 8, Faudoa teaches that, “[f]or administration of collagenase, for example, MMP-1, the dosage can be in the range of about 5 μg to about 50 mg/kg of tissue to which the application is directed” (see pg. 29, para. [0300]). Faudoa further discloses that, “[a]mounts and concentrations of each agent are known in the art and the appropriate dosage may be found by no more than routine experimentation” (see pg. 22, para. [0218]). Faudoa also teaches the collagenase may have an activity of greater than 50 U/mg (see pg. 3, para. [0027]).
For example, if one were to apply Faudoa’s teachings in a patient having 1.0 kg of lung tissue, at a dose 50 mg/kg of tissue, and an enzyme activity of 50 U/mg of collagenase, a person of skill may arrive at dose of 50 mg with a total activity of 2,500 U. In a patient weighing 62 kg, this would equate to a dosage of 0.83 mg/kg of body weight with an enzyme activity of about 40 U/kg of body weight. However, Faudoa also teaches the purity of the collagenase may vary and the enzyme activity may be lower, such as 5.0, 10 or 20 U/mg (see pg. 3, para. [0027]). Therefore, in order to achieve the same effect as the dose of 0.83 mg/kg having 40 U/kg of activity, the dosage may be adjusted to 8, 4, or 2 mg/kg of body weight, respectively, to accommodate the lower activity of the enzyme. Hence, a person of skill would reasonably arrive at doses that fall within the claimed parameter through no more than routine optimization.
Hence, Faudoa provides a result-effective variable as a starting point in mg/kg of tissue for a person of ordinary skill to have arrived at the claimed ranges in mg/kg of patient body weight through no more than routine optimization, and there is no disclosure of unexpected results in the instant specification to support that the claimed range was critical.
Regarding claim 10, Faudoa teaches that the subject or individual may be a human or an animal (see pg. 21, para. [0204]).
Regarding claim 11, Faudoa teaches that the collagenase is “MMP-1” (see pg. 2, para. [0019]).
Regarding claim 21, the claim is the same as claim 1, except for the limitation of “wherein the dosage of aerosolized collagenase administered is about 3, 4, 5, 6, 7, 8, 9, or 10 mg/kg of the patient’s body weight.” Hence, for the reasons discussed regarding claim 8, a person of skill would have reasonably arrived at doses that fall within the claimed parameter through no more than routine optimization. Faudoa provides a result-effective variable as a starting point in mg/kg of tissue for a person of ordinary skill to have arrived at the claimed ranges in mg/kg of patient body weight through no more than routine optimization, and there is no disclosure of unexpected results in the instant specification to support that the claimed range was critical.
Regarding claim 22, the claim is obvious for the same reasons discussed regarding claims 8 and 21.
Claims 2-3, 12, 16-17 and 19 are rejected under 35 U.S.C 103 as being unpatentable over Faudoa, as applied to claims 1, 4-5, 8, 10-12 and 16-17, 19, and 21-22 above, and in further view of Rafii, US 20130224161 A1 (previously cited).
Regarding claim 2, Faudoa teaches a method of treating internal wounds, such as a lung lesion, by the administration of a collagenase, such as MMP1, by use of an aerosolized spray, as discussed above.
Faudoa does not teach the method wherein the acute lung injury is acute respiratory distress syndrome (ARDS).
Raffii teaches “a method to enhance or induce organ regeneration in a subject in need thereof comprising administering one or more of…MMP14…to said subject in an amount sufficient to enhance or induce organ regeneration in said subject” and further, “wherein the organ is the lung” (see pg. 2, para. [0017]). Raffii teaches that “[t]he lung regeneration induced by the methods of this invention will be useful in treating various lung diseases and injuries where lung function is impaired or lung capacity is reduced” and “lung diseases that could be treated with these methods include, but are not limited to, Adult Respiratory Distress Syndrome (ARDS)” (see pg. 10, para. [0104]). Note that “Adult Respiratory Distress Syndrome” and “Acute Respiratory Distress Syndrome” refer to the same syndrome, and are equivalent. Raffi also teaches the method can be used to treat “post-traumatic ARDS” and other acute lung injuries, such as, COPD, lung cancer, asthma, emphysema, etc. (see pg. 10, para. [0104]). Raffi teaches that MMP14 promotes regenerative alveolarization in the lungs, and thus, endothelial cells which express MMP14 can be therapeutically exploited for the treatment of lung disorders (see pg. 18, para. [0172]).
It would have been obvious at the time of filing for a person of ordinary skill in the art to have arrived at the claimed invention by modifying the method taught by Faudoa for the treatment of ARDS, because Raffii suggests that the use of collagenases, such as MMP14, may be useful in treating ARDS. One would have recognized that Faudoa teaches a method of treating lung injuries that are in need of repair and/or regeneration, comprising administration of one or more collagenases, while Raffii teaches a similar method of regenerating injured lungs by administering MMP14. One would have been particularly motivated to combine these teachings, because Raffi teaches that MMP14 is therapeutically effective in the regeneration of lung tissue to treat conditions, such as ARDS. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Regarding claim 3, Raffi teaches the method wherein the lung disease is Chronic Obstructive Pulmonary Distress syndrome (COPD) (see pg. 10, para. [0104]).
Regarding claim 12, Raffi teaches the method wherein the lung disease is ARDS, including post-traumatic ARDS, or another acute lung injury, such as COPD, lung cancer, asthma, or emphysema, as discussed above. Faudoa teaches that “a prophylactic benefit of treatment includes prevention of a condition, retarding the progress of a condition (e.g., slowing the progression of a chronic wound), or decreasing the likelihood of occurrence of a condition. As used herein, ‘treating’ or ‘treatment’ includes prophylaxis” (see pg. 2, para. [0202]).
Note that apart from what is recited in the preamble (“A method of preventing acute respiratory distress syndrome (ARDS), pulmonary fibrosis, or both in a patient susceptible to having an acute lung injury”) and the recited effects of administering (“… such that the ARDS, pulmonary fibrosis, or both is prevented”), the body of the claim recites the same method steps as claim 1.
During examination, statements in the preamble reciting the purpose or intended use of the claimed invention must be evaluated to determine whether or not the recited purpose or intended use results in a structural difference (or, in the case of process claims, manipulative difference) between the claimed invention and the prior art. If so, the recitation serves to limit the claim. See, e.g., In re Otto, 312 F.2d 937, 938, 136 USPQ 458, 459 (CCPA 1963). As discussed under 35 U.S.C. 112(b), “a patient susceptible to having an acute lung injury” is interpreted to be any patient. When considering the preamble of the claim, the “patient” recited in the claim does not (yet) have acute respiratory distress syndrome (ARDS) or pulmonary fibrosis. Hence, the preamble of the claim does not limit the identity of the “patient” and is directed to an intended use (to prevent ARDS and/or pulmonary fibrosis) in any patient, and, further, does not provide any limitation to any structure or method step recited in the body of the claim to amount to a “manipulative difference”.
The recitation of “such that the ARDS, pulmonary fibrosis, or both are prevented” is a functional limitation which also does not limit any structure or method step in the claimed process. Hence, the prevention of ARDS and/or pulmonary fibrosis is directed to an inherent property that does not affect the structure or steps of the claimed invention. See MPEP 2112(IV) which states:
"[I]n order to rely on inherency to establish the existence of a claim limitation in the prior art in an obviousness analysis – the limitation at issue necessarily must be present, or the natural result of the combination of elements explicitly disclosed by the prior art." Id. at 1195-96, 112 USPQ2d at 1952. But see, Persion Pharms. LLC v. Alvogen Malta Operations LTD., 945 F.3d 1184, 1191, 2019 USPQ2d 494084 (Fed. Cir. 2019), where the court stated that a proper finding of inherency does not require that all limitations are taught in a single reference, and that inherency may meet a missing claim limitation when the limitation is "the natural result of the combination of prior art elements." (emphasis in original). The court found that pharmacokinetic limitations of the asserted claims were inherently met by combining prior art references because the limitations were necessarily present in the prior art combination. Id. See also Hospira, Inc. v. Fresenius Kabi USA, LLC, 946 F.3d 1322, 1329-32, 2020 USPQ2d 6227 (Fed. Cir. 2020).
Because the remainder of the claim recites the same structure and steps as instant claim 1, the functional limitations of the claimed method are necessarily present in the prior art combination, and are inherently met by the combination of references. See MPEP 2112. Furthermore, Raffi teaches the administration of collagenases to patients having an acute lung injury (including ARDS), and Faudoa suggests that the administration of collagenases may be preventative. Hence, the claim is obvious for the same reasons discussed regarding claims 1 and 2.
Regarding claim 16, the instant claim is obvious for the same reasons discussed regarding for claims 5 and 12.
Regarding claim 17, the instant claim is obvious for the same reasons discussed regarding claims 11 and 12.
Regarding claim 19, the claim is obvious for the same reasons discussed regarding claims 8 and 12.
Claim 7 is rejected under 35 U.S.C 103 as being unpatentable over Faudoa, as applied to the claims 1, 4-5, 8, 10-11 and 21-22 above, and in further view of Fröhlich et al. (previously cited), hereafter “Frohlich”.
Regarding claim 7, it would have been obvious to have administered the aerosol spray of Faudoa by oral inhalation, as discussed regarding claims 1 and 5.
Faudoa does not explicitly teach “wherein the aerosolized collagenase has a diameter of about 0.1-10 µm”.
Frohlich teaches that oral inhalation is the preferred route for delivery of small molecules to the lungs (see Abstract) and lung diseases such as asthma, COPD, and cystic fibrosis are traditionally treated with small molecules administered by oral inhalation (see pg. 198, col. 1, para. 1). In view of the instant claims, “COPD” and “cystic fibrosis” are acute lung injuries. Frohlich teaches that most inhaled biologics are liquid suspensions of the proteins/peptides without modifications, and delivery is mainly determined by aerosol droplet deposition (see pg. 203, col. 1, para. 1). Frohlich teaches that particles with an aerodynamic diameter greater than 10 µm deposit in the extrathoracic region (nose, mouth, pharynx, larynx), while particles between 2 and 10 µm deposit in the tracheobronchial tree (see pg. 199, col. 1, para. 1). Frohlich also teaches that nebulizers are the most commonly used devices for pulmonary administration of biologics, and three types of nebulizers are commercially available to generate 1-5 μm droplets (see pg. 201, col. 2, para. 3).
It would have been obvious at the time of filing for a person of ordinary skill in the art to have arrived at the claimed invention by combining the teachings of Faudoa and Frohlich, because both references teach methods of delivering therapeutic proteins to the lungs by oral inhalation to treat lung diseases. One of ordinary skill would have recognized from Frohlich that particles between 2 and 10 µm are more likely to deposit in the lungs, while particles greater than 10 µm are more likely to deposit in the extrathoracic region. Hence, it would have been prima facie obvious to have selected a particle size within the reference range of 2-10 µm when administering the aerosolized collagenase of Faudoa. Because Faudoa discloses a method for administering collagenases in a highly purified form via the aerosol route to the lungs, a person skilled in the art would have found it prima facie obvious at the time of filing to use the prior art range, which lies entirely within the claimed range, when using the method taught by Faudoa. See MPEP § 2144.05, Obviousness of Similar and Overlapping Ranges, Amounts, and Proportions - which states that, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
Claim 9 is rejected under 35 U.S.C 103 as being unpatentable over Faudoa, as applied to claims 1, 4-5, 8, 10-11 and 21-22 above, and in further view of Ingenito, US 2005024401 A1 (previously cited).
Regarding Claim 9, the method of claim 1 is obvious over Faudoa, as discussed above
Faudoa does not explicitly teach “wherein one or more collagenase is administered using an ultrasonic nebulizer”.
Ingenito discloses, “methods that can be used to damage (e.g., to selectively ablate) epithelial cells (e.g., those in an epithelial cell layer) in an organ, such as the lung… methods for effecting epithelial damage can be used to treat patients who have certain diseases of the lung, such as emphysema (a chronic obstructive pulmonary disease (COPD))” (see pg. 5, para. [0031]), or wherein the lung has been damaged by a traumatic event (see pg. 3, para. [0014]). Ingenito teaches said methods comprising administering a collagenase to the patient’s lung (see claim 9). Ingenito further discloses that, “[t]he delivery apparatus can also be a nebulizer…Nebulizers are known in the art and can be…an ultrasonic nebulizer” (see pg. 16, para. [0132]). Ingenito teaches that nebulizers are commonly used to deliver substances to the pulmonary air passages (see pg. 16, para. [0133]).
It would have been obvious at the time of filing for a person of ordinary skill in the art to have modified the method of Faudoa to include the ultrasonic nebulizer taught by Ingenito to achieve the same benefit of delivering the one or more collagenases to the lungs of a patient with an acute lung injury such as COPD or lung damage due to trauma. This is because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention. (As described in MPEP § 2143, Section A. Combining Prior Art Elements According to Known Methods To Yield Predictable Results). One would have been motivated to combine these teachings, because both references teach the therapeutic benefits of delivering collagenases to the lungs of patients who have acute lung injuries. Furthermore, it is well within the ordinary skill in the art to administer therapeutic proteins to the lungs using devices commonly known in the art.
Claim 18 is rejected under 35 U.S.C 103 as being unpatentable over Faudoa and Raffi, as applied to the claims 12, 16-17 and 19 above, and in further view of Frohlich.
Regarding claim 18, the method of claim 12 is obvious over Faudoa and Raffi, as discussed above. Further, it would have been obvious to have administered the aerosol spray of Faudoa by oral inhalation, as discussed regarding claims 1 and 5.
Faudoa does not explicitly teach “wherein the aerosolized collagenase has a diameter of about 0.1-10 µm”.
Frohlich, as previously discussed, teaches that oral inhalation is the preferred route for delivery of small molecules to the lungs (see Abstract) and lung diseases such as asthma, COPD, and cystic fibrosis are traditionally treated with small molecules administered by oral inhalation (see pg. 198, col. 1, para. 1), which are acute lung injuries. Frohlich teaches that most inhaled biologics are liquid suspensions of the proteins/peptides without modifications, and delivery is mainly determined by aerosol droplet deposition (see pg. 203, col. 1, para. 1). Frohlich teaches that particles with an aerodynamic diameter greater than 10 µm deposit in the extrathoracic region (nose, mouth, pharynx, larynx), while particles between 2 and 10 µm deposit in the tracheobronchial tree (see pg. 199, col. 1, para. 1). Frohlich also teaches that nebulizers are the most commonly used devices for pulmonary administration of biologics, and three types of nebulizers are commercially available to generate 1-5 μm droplets (see pg. 201, col. 2, para. 3).
It would have been obvious at the time of filing for a person of ordinary skill in the art to have arrived at the claimed invention by combining the teachings of Faudoa, Raffi and Frohlich, because all references relate to methods of delivering therapeutic proteins to the lungs by oral inhalation to treat lung diseases. One of ordinary skill would have recognized from Frohlich that particles between 2 and 10 µm are more likely to deposit in the lungs, while particles greater than 10 µm are more likely to deposit in the extrathoracic region. Hence, it would have been prima facie obvious to have selected a particle size within the reference range of 2-10 µm when administering the aerosolized collagenase of Faudoa. Because Faudoa discloses a method for administering collagenases in a highly purified form via the aerosol route to the lungs, a person skilled in the art would have found it prima facie obvious at the time of filing to use the prior art range, which lies entirely within the claimed range, when using the method taught by Faudoa. See MPEP § 2144.05, Obviousness of Similar and Overlapping Ranges, Amounts, and Proportions - which states that, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
Response to Amendment
The declarations under 37 CFR 1.132 filed 10/21/2025 are insufficient to overcome the rejection of claims 1-5, 7-12, 16-19 and 21-22 under 35 U.S.C. 103 as set forth in the last Office action because:
(1) They refer only to the general disclosure of the present application and not to the individual claims of the application. As such, the declarations do not show any objective evidence of nonobviousness that is commensurate in scope with the claims. Further, the declarations do not address any of the teachings of the references used in the rejections or make any comparison between the claimed invention and the closest prior art. See MPEP § 716.
(2) They allege unexpected results without presenting any objective evidence (i.e., factual data) or any comparison to the closest prior art. See, for example, In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984) ("It is well settled that unexpected results must be established by factual evidence."). In the instant case, each declaration presents an expert opinion regarding the difficulties and challenges of administering collagenases to treat the conditions of the claims, while also alleging that the claimed invention provides new and unexpected results. However, there is no objective evidence presented in the declarations to show that the claimed features of the invention do, in fact, overcome the challenges described, let alone any comparative data between the claimed invention and the closest prior art. See further, MPEP 716.01(c) (“Probative Value of Objective Evidence”) and MPEP 716.02 (“Unexpected Results”).
(3) They allege that the claimed subject matter may solve a problem that was long standing in the art. However, there is no showing that others of ordinary skill in the art were working on the problem and if so, for how long. Moreover, there is no evidence presented to show that if persons skilled in the art, who were presumably working on the problem, knew of the teachings of the above cited references, they would still be unable to solve the problem. See MPEP 716.04 (“Long-Felt Need and Failure of Others”).
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Response to Arguments
Applicant's arguments filed 10/21/2025 have been fully considered but they are not persuasive.
Regarding the rejection of claim 12 under 35 U.S.C. 112(b), Applicant states that the amendments to the claim are believed to address the rejection.
Applicant’s arguments have been fully considered but are not persuasive, because the basis for the rejection in the previous Office Action was the recitation of the term “susceptible” which is still recited in the claim and is recited in the same context (i.e., “in a patient susceptible to having an acute lung injury”) as in the previous claim. See the present rejection under 35 U.S.C. 112(b) for further discussion.
Regarding the rejection of claims 12 and 14-19 under 35 USC 112(a) for failing to meet the enablement requirement, Applicant states that the amendments to claim 12 are believed to be enabled in view of the amendments.
Applicant’s arguments have been fully considered but are not persuasive for the following reasons. The claim was previously directed to preventing any acute lung injury. As discussed under the present rejections under 112(b) and 112(a), the amended claim is now directed to preventing ARDS and/or pulmonary fibrosis in a patient that is “susceptible” to having any acute lung injury, which is broadly interpreted to include any patient. For the reasons discussed under the present rejection under 112(a), the specification is not considered to be enabled for this scope.
Regarding the rejections under 35 U.S.C. 103, Applicant argues that Faudoa is concerned with wound debridement, oral care, cosmetics, and cell culture, not pulmonary disease.
Applicant’s argument is not persuasive, because Faudoa also relates to methods of treating internal injuries to the lungs by the administration of MMP-1, as discussed in the rejection. “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). Further, “[a] reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See MPEP 2123. In the instant case, a person of ordinary skill would have been able to draw from any aspect of Faudoa’s disclosure, including from Faudoa’s definition of a wound, which includes “other epithelium” (apart from skin), “airway/lung lesions”, and “other internal wounds” (see pg. 20, para. [0199]) which reasonably suggests that MMP-1 may be used to treat pulmonary injuries, such as lung lesions.
Applicant specifically argues “there is no discussion or suggestion of administration to the lung, no mention of acute lung injury (ALI), Pulmonary Fibrosis or acute respiratory distress syndrome (ARDS)” in Faudoa.
Applicant’s arguments have been fully considered but are not persuasive for the following reasons.
(1) Faudoa’ teaches that wounds include injuries to the lungs, as discussed above.
(2) Faudoa’s teaches “direct delivery” by “pulmonary administration” and the use of an “aerosol”, as discussed in the rejection of claim 1.
(3) Faudoa teaches the method is useful in enhancing the repair of “traumatic” tissue damage, as discussed in the rejection of claim 4. The instant claim explicitly includes “trauma to the lung tissue” as an acute lung injury, as does Applicant’s disclosure.
(4) Independent claims 1 and 21 do not recite “ARDS” or “pulmonary fibrosis”. Hence, the majority of the claims do not even recite/require these features. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
(5) In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, additional references are relied upon regarding the claims which are directed to “ARDS”.
Applicant specifically argues “a prior art reference that is directed to a different field or solves a different problem is not ‘analogous art’ and therefore cannot support a rejection under §103.” Further, “Faudoa is neither in the same field as the present invention nor reasonably pertinent to the pulmonary therapeutic or prophylactic problems addressed by claims 1 and 12.”
Applicant’s arguments have been fully considered but they are not persuasive. In response to applicant's argument that Faudoa is nonanalogous art, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, Faudoa relates to medical treatments comprising the administration of collagenases to treat wounds, including pulmonary injuries (i.e., lung injuries), and is reasonably pertinent to the problem of treating acute lung injuries by the administration of said collagenases.
Applicant further argues that Faudoa’s concentration-based disclosures are “fundamentally different” from the claimed “activity-based” dose. Faudoa discloses only concentrations expressed in terms of % w/w of a composition, mg/gm, U/gm of formulation, or µg/kg of tissue - parameters that are not interchangeable with, and cannot reasonably be converted into, the claimed units of enzymatic activity per kilogram of patient body weight.
Applicant’s arguments have been fully considered but they are not persuasive for the following reasons.
(1) Faudoa does teach “activity-based” doses in U/mg of collagenase activity which Faudoa teaches may depend on the purity of the enzyme, as discussed in the present rejection.
(2) It is within the ordinary skill in the art to determine the activity of an enzyme and the concentration can be routinely optimized to have arrived at an effective dose, as discussed in the rejection. Further, Faudoa provides a result-effective variable in mg/kg of tissue which would necessarily correlate to doses in mg/kg and U/kg of body weight that include the claimed doses.
(3) Applicant’s allegation that such concentrations and doses are “fundamentally different” and “cannot reasonably converted” it is not based on a factual conclusion. For example, all enzymes utilized for their “activity” must have some level of “activity”. This is an inherent property of any active enzyme which can be determined by an ordinary artisan. Further, the weight of an affected tissue (e.g., the lungs) is something that is known in the art, and the weight of an individual can be readily assessed in a clinical setting. Hence, Applicant’s argument that these variables are “fundamentally” unrelated is unclear without further evidence to support this assertion.
Applicant further argues that although Faudoa briefly mentions the use of an “aerosol spray,” such disclosure is expressly directed to topical cosmetic or dermatologic applications—not for inhalation or pulmonary administration. Further, there is no teaching or suggestion in Faudoa of aerosol delivery intended for deposition within the lung or for treatment of pulmonary tissue.
Applicant’s arguments have been fully considered but they are not persuasive. See page 22, paragraph [0215] of Faudoa which states:
The wound to which the therapeutic combinations are applied can be internal or external, and may be directed towards any tissue exhibiting a wound, for example epithelial tissue. Other modes of administration include injection, either subcutaneously, intradermally, intraperitoneally, intraluminally, intragastrically, intraintestinally, intravenously or intramuscularly. Dosage treatment may be a single dose schedule or a multiple dose schedule. Administration of the therapeutic combinations of the invention can be accomplished by, for example, topical cream, foam, injection, aerosol spray, in a gel matrix, a sponge, drops, and a wash. Administration can be by, for example, local, oral, intradermal, subcutaneous, intraluminal, intragastric, and intraperitoneal administration with an appropriate formulation of the selected composition made up of a combination of the therapeutics appropriate for a particular treatment.
Hence, Faudoa’s mention of an “aerosol spray” is not “expressly directed” to only “topical cosmetic or dermatologic applications”, because Faudoa presents this teaching in the context of treating any wound, including internal wounds, and expressly recites routes of administration that are not “topical cosmetic or dermatologic” in nature, such as intraluminal injections. In combination with Faudoa’s other teachings, as discussed in the rejection and in the arguments above, Faudoa disclosure reasonably suggests that the treatment of lesions within the lungs may be treated by administering collagenases using an aerosol spray. Furthermore, a person of ordinary skill would not reasonably conclude from Faudoa that the “lung lesion” of the disclosure can be treated by a “dermatologic” administration.
Regarding the finding that Faudoa teaches a result-effective variable, Applicant argues that “[t]he Federal Circuit has repeatedly held that a new dosing regimen, especially one measured in a different way or normalized to a different variable, can support a finding of non-obviousness when it is not suggested by the prior art. See, e.g., In re Antonie, 559 F.2d 618, 620 (CCPA 1977) (routine optimization cannot supply obviousness when the parameter itself is not recognized in the prior art); Allergan, Inc. v. Sandoz Inc., 796 F.3d 1293, 1305 (Fed. Cir. 2015) (differences in dosing schedule and measurement supported non-obviousness even where the active agent was known); Sanofi-Synthelabo v. Apotex, Inc., 550 F.3d 1075, 1086 (Fed. Cir. 2008) (a new dosing regimen that produced unexpected results was non-obvious over prior art disclosing the same compound).”
Applicant’s arguments have been fully considered but they are not persuasive, because the variable of enzyme activity is recognized by Faudoa as affecting the relevant properties of the collagenase. See MPEP 2144.05(III)(C):
For example, in Antonie the claimed device was characterized by a certain ratio, and the prior art did not disclose that ratio and was silent regarding one of the variables in the ratio. Id. at 619. Our predecessor court thus reversed the Board’s conclusion of obviousness. Id. at 620. Antonie described the situation where a ‘parameter optimized was not recognized to be a result-effective variable’ as an ‘exception' to the general principle in Aller that 'the discovery of an optimum value of a variable in a known process is normally obvious.’ Id. at 620. Our subsequent cases have confirmed that this exception is a narrow one. … In summarizing the relevant precedent from our predecessor court, we observed in Applied Materials that ‘[i]n cases in which the disclosure in the prior art was insufficient to find a variable result-effective, there was essentially no disclosure of the relationship between the variable and the result in the prior art.' 692 F.3d at 1297. Likewise, if the prior art does recognize that the variable affects the relevant property or result, then the variable is result-effective. Id. (emphasis added)
In the instant case, Faudoa recognizes that the activity of the enzyme (U) affects the relevant property or result of the collagenase by disclosing desired activity levels in U/mg. Faudoa further states that factors “which influence what a therapeutically effective amount will be” include “the specific activity of the therapeutic agent being used” (see pg. 20, para. [0203]). Hence, Applicant’s rebuttal fails to meet the narrow exception described in Antonie, because the claimed dosing parameter involves variables that are recognized in the prior art as affecting the enzyme’s effects and can be routinely used to determine a therapeutically effective amount.
Applicant argues that Faudoa explicitly and repeatedly relies on cAMP-elevating agents as essential co-components of its compositions. Specifically, Faudoa consistently teaches that collagenase (including MMP-1) should be co-administered with agents that raise intracellular cyclic AMP (cAMP), such as forskolin, 3-isobutyl-1-methylxanthine (IBMX), or theophylline, and that the relative ratios between these components are important to achieving the desired biological effects. The present invention achieves its therapeutic (claim 1) and prophylactic (claim 12) results without the use of any cAMP-modulating agents.
Applicant’s arguments have been fully considered but they are not persuasive.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., the absence of cAMP-elevating agents) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In the instant case, the scope of the claims do not exclude the co-administration of other agents.
Applicant further argues that Faudoa teaches away from the methods of claims 1 and 12, stating that the reference explicitly warns of cellular toxicity and fibroblast apoptosis when collagenase (MMP-1) is used in combination with cAMP elevating agents. Faudoa makes clear that such combinations can lead to cell death in mammalian cells in vitro. Applicant supports this argument by stating, “Faudoa expressly reports that treatment of cultured fibroblasts with MMP-1 in combination with cAMP-elevating agents such as forskolin or IBMX resulted in induction of apoptosis and loss of cell viability (see, e.g., column 9, lines 20-30; column 10, lines 1-10). The reference describes these effects as a consequence of the enzyme's action on extracellular matrix components and downstream signaling pathways. It notes that such treatment ‘can induce programmed cell death’ and that fibroblast proliferation was inhibited ( column 10, lines 11-20).”
The examiner is not able to consider the evidence presented in support for Applicant’s argument, because the passages that Applicant refers to cannot be found as cited above. For instance, the published patent application (PG-PUB) of Faudoa does not recite “column” or “line” numbers. Further, the direct quote “can induce programmed cell death” is not found anywhere in the reference.
Applicant further argues that Applicant’s disclosure provides unexpected results. Applicant states that “[t]hese results are documented and discussed throughout the specification as filed”. Applicant specifically cites: Figs. 11a-11d; page 22, lines 3-20; page 8, line 14, through page 9, line 5; page 14, lines 16-30; and page 15, lines 16-26.
Applicant’s arguments have been fully considered but they are not persuasive, because Applicant’s assertion of unexpected results constitute mere argument. "It is well settled that unexpected results must be established by factual evidence." In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). “[A]ppellants have not presented any experimental data showing that prior heat-shrinkable articles split. Due to the absence of tests comparing appellant’s heat shrinkable articles with those of the closest prior art, we conclude that appellant’s assertions of unexpected results constitute mere argument.”). See also In re Lindner, 457 F.2d 506, 508, 173 USPQ 356, 358 (CCPA 1972); Ex parte George, 21 USPQ2d 1058 (Bd. Pat. App. & Inter. 1991). See also MPEP 716.01(c) which states that to be of probative value any objective evidence must be supported by actual proof. In the instant case, none of the passages cited above, nor any passage in Applicant’s disclosure, provide any factual evidence in support of unexpected results. To be persuasive, arguments which allege nonobviousness based on unexpected results must be supported by evidence, such as experimental data, showing a side-by-side comparison with the closest prior art.
Applicant further argues that a substantial body of scientific and clinical literature consistently warned against the very approach embodied in the present invention; that the literature shows that developing any inhaled biologic therapy is complex, failure-prone, and unpredictable; and attempts to treat ARDS and pulmonary fibrosis have been similarly unsuccessful. Applicant argues that past efforts with inhaled proteases further underscore the unexpected nature of Applicant’s success.
Applicant’s arguments have been fully considered but they are not persuasive, because no objective evidence of any probative value has been presented to support Applicant’s “unexpected” success. Furthermore, Applicant does not specifically point out which features recited in the claims overcome the unpredictability that is present in the prior art.
Regarding the rejections over Faudoa in view of Rafii, Applicant argues that Rafii appears to be limited to a method for organ regeneration and, at best, teaches treating wounds of the lungs by administering one or more EGF-receptor ligands selected from a group that includes MMP14. Further, Rafii teaches the use of MMP14 by application to tissue samples of various organs to isolate stem cells, growth factors, and endothelial cells.
Applicant’s argument has been fully considered but they are not persuasive.
(1) In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Raffi suggests the use of a compound that is acknowledged by the present disclosure to be within the scope of a “collagenase” to treat acute lung injuries, such as ARDS, COPD, lung cancer, asthma, and emphysema, as discussed in the present rejection.
(2) “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). Further, “[a] reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See MPEP 2123. In the instant case, Raffi teaches that MMP14 promotes regenerative alveolarization in the lungs, and thus, endothelial cells which express MMP14 can be therapeutically exploited for the treatment of lung disorders, as discussed in the present rejection.
Applicant further argues that the “determination of obviousness cannot be established by combining teachings of the prior art to produce the claimed invention, absent some specific teaching, suggestion or incentive supporting this combination, as is further highlighted in (In re Avery, 518 F.2d 1228, 186 USPQ 161 (CCPA 1975). Applicant submits that the use claimed and taught by Rafii is completely outside of the scope of the claimed subject matter, with no specific teaching or incentive to combine these teachings or references, (In re Vaeck, 947 F.2d 488 (Fed. Cir. 1991 ), thereby negating any alleged obviousness, as it would not have been obvious to combine these prior arts, from completely unrelated fields and scopes.
Applicant’s arguments have been fully considered but they are not persuasive for the following reasons.
(1) Both Faudoa and Raffi teach collagenases (MMP1 and MMP14, respectively) for the treatment of acute lung injuries (lung lesions and ARDS, respectively), Faudoa further teaching the use of an aerosol spray and the teaching of pulmonary administration. Hence, both references contain some specific teaching to support the combination.
(2) The use of MMP-1 taught by Rafii is not outside the scope of the claimed subject matter or that of Rafii. Both references contain subject matter that relates to administering a collagenase to treat conditions that are within the scope of “an acute lung injury”.
(3) Both references pertain to methods of administering bio-affecting and body treating compositions to repair tissue damage in the lungs, wherein the compositions of both references include collagenases. Hence, Faudoa and Rafii are evidently in the same field of endeavor and are within the same scope.
Regarding the rejections of claims 7 and 18 over Faudoa in view of Frohlich, Applicant argues this reference fails to disclose, suggest, or even contemplate aerosolized administration of collagenase to the lung for the treatment or prevention of acute lung injury, ARDS, or pulmonary fibrosis. Furthermore, Frohlich contains no teaching of dosing in terms of enzymatic activity per kilogram of patient body weight, nor does it provide any motivation to employ collagenase in the delicate pulmonary environment without cAMPelevating agents - let alone to expect the unexpected clinical benefits that Applicant's invention achieves, such as improved pulmonary compliance, reduced fibrotic
remodeling, and preservation of viable tissue.
Applicant’s arguments have been fully considered but they are not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Frohlich is relied upon for the reference’s relevant teachings of the pulmonary administration of therapeutic biologics by inhalation for the treatment of acute lung injuries. Hence, Frohlich is clearly relevant to the aerosolized administration of collagenase to the lung (taught by Faudoa) for the treatment of acute lung injuries. Applicant’s arguments regarding dosing and cAMP-elevating agents have been fully addressed above, regarding Faudoa.
Applicant argues that while the mention of particle size necessary to reach the alveolar region are mentioned in Frohlich as a general guideline, this particle size does not guarantee a set therapeutic effect or response across different compounds. For example, different compounds nebulized at a particle size of 1 to 5 um will have different biochemical and physiologic effects despite having similar particle size upon nebulization. Hence, there is no “guarantee” of a comparable and similar response as this is inherent to the compound that is being inhaled.
Applicant’s argument is not persuasive, because obviousness only requires a reasonable expectation of success, not a “guarantee”. The prior art of Frohlich teaches the use of compounds nebulized at a particle size that is within the claimed range, which provides the ordinary artisan a reasonable expectation to achieve the desired results.
Applicant further argues that the reference provides no evidence that a person of ordinary skill would have had a reasonable expectation of success in aerosolizing collagenase for therapeutic pulmonary use. To the contrary, it lacks disclosure regarding formulation stability, aerosol delivery challenges, or safety considerations specific to inhaled proteases. Thus, when read together with Faudoa, the reference still leaves unaddressed the key distinctions and deficiencies outlined above.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., formulation stability, aerosol delivery challenges, or safety considerations) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Specifically, Applicant fails to point which features of the claimed invention address the challenges above, or how these features overcome each of these challenges.
Regarding the rejections over Faudoa in view of Ingenito, Applicant argues that Ingenito appears to be limited to methods for performing non-surgical lung volume reduction in a patient by administering a composition comprising an enzyme, detergent, and/or polycation. Applicant argues that the entire premise of Ingenito is to treat COPD or lungs with excessively floppy or compliant lungs. Applicant argues that Ingenito teaches that use of collagenase will be used to cause worsening compliance and fibrosis, via damaging the lung with collagenase. Ingenito is therefore teaching away from the use of collagenase in an inhaled nebulized from in accordance with independent claim 1.
Applicant’s argument is not persuasive, because “[t]he use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). In the instant case, Ingenito teaches the use of an ultrasonic nebulizer to administer collagenases to the lungs of a patient with acute lung injury, such as COPD or lung damage due to trauma. A skilled artisan would have recognized from this prior art teaching that an ultrasonic nebulizer could be used to administer collagenases to the lungs in accordance with Faudoa’s methods. See also MPEP 2123(II) which states, “Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971).”
Conclusion
No claims are allowed.
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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/DENNIS IGNATIUS ARMATO JR/Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651