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 .
Response to Amendment
Applicant’s response filed 08 October 2025 has been received and entered. Claims 1, 33 and 50 have been amended, claims 2-4, 9, 12-32, 34-49 and 61-62 have been canceled and claims 63-68 have been newly added. Claims 1, 5-8, 10-11, 33, 50-60 and 63-68 are currently pending and under consideration in the instant Office action.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Any objection or rejection of record which is not expressly repeated in this action has been overcome by Applicant’s response and withdrawn.
Applicant’s arguments filed 08 October 2025 have been fully considered but are not found to be persuasive.
NOTE: It has come to the attention of the Examiner that the correct spelling for the inventor of US Pat Pub 2008/0066741 is LeMahieu et al. and not MeMahieu et al. This was an obvious typographical error which has been corrected.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08 October 2025 has been considered by the examiner.
Specification
The title of the invention is still not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
Response to Arguments
Applicant requests that any additional objection to the title be held in abeyance until allowable subject matter is identified. Applicant’s request is not proper as there is no basis for holding this objection in abeyance. A sufficiently descriptive title could be provided, such as method of stimulating lung growth by administration of VEGF-A via respiratory tract which would be satisfactory.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1, 6 and 64 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Carmeliet et al. (WO2016/198121).
Carmeliet et al. teach the treatment of subjects suffering from lung hypoplasia, specifically directed to subjects with congenital diaphragmatic hernia (CDH), by the administration of VEGF-A. Carmeliet et al. administered nanodiamond particles chemically conjugated to VEGF in an experimental model of CDH wherein the VEGF was administered by intra-pulmonary delivery in utero. The prenatal intra-pulmonary delivery of VEGF induced “dramatic lung growth” (see Example 1 at page 6) as well as increased alveolar size and thinner alveolar septa. The VEGF molecule which was administered is VEGF164, which is the rodent isoform equivalent of human VEGF165.
Response to Arguments
The above rejection is newly made as claim 1 has been amended to remove the limitation that administration is by inhalation. Therefore, the new rejection was necessitated by the amendment. As such, there are no arguments which directly apply to the anticipation rejection.
Applicant does argue the Carmeliet et al. reference at page 11 of the response. Applicant asserts that the Examiner’s statement:
Carmeliet et al. teach the treatment of subjects suffering from lung hypoplasia, specifically directed to subjects with congenital diaphragmatic hernia (CDH), by the administration of VEGF-A and that such treatment (prenatal intra-pulmonary delivery of VEGF) results in dramatic lung growth
is inaccurate and that “no such teaching is present in Carmeliet” and that “Carmeliet could be considered to teach away from the presently claimed methods”.
Applicant’s arguments have been fully considered, but are not found persuasive. Example 1 of Carmeliet et al. describe improvement in lung growth in an experimental congenital diaphragmatic hernia model. The CDH model results in lung hypoplasia, therefore, the subjects of Carmeliet et al. meet the limitations of the claims as the subjects would be in need of promoting lung growth. Carmeliet et al. administered a composition comprising VEGF (which is VEGF-A (see page 5, line 20)) intratracheally and the trachea is part of the respiratory tract. Carmeliet et al. conclude that prenatal intra-pulmonary delivery of VEGF induced dramatic lung growth in their experimental model of CDH (bottom of page 6).
Applicant asserts at pages 11-12 of the response that Carmeliet et al. teach a combination therapy involving tracheal occlusion and administration of a conjugated, nanoparticle-bound VEGF and unbound VEGF did not provide a therapeutic effect. Applicant’s arguments have been fully considered, but are not found persuasive. The claims which are anticipated require administering an effective amount of a composition comprising VEGF-A wherein the composition is administered through respiratory tract. Carmeliet et al. meets the limitations of the above cited claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, 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.
Claim(s) 1, 5-8, 33, 63 and 65-66 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rafii (US Pat Pub 2013/0224161 A1) in view of Ruediger et al. (US Pat Pub 2006/0040860).
Rafii teach a method of inducing organ regeneration in a subject in need thereof wherein the organ is the lung by administering VEGF-A to enhance or induce organ regeneration (see [0017]. Rafii teach that lung diseases which could be treated include but are not limited to lung hypoplasia, lung trauma, pulmonary hypoplasia, lung injury, and bronchopulmonary dysplasia (see [0104]-[0105]). Rafii also teaches that the method provides for alveolarization in a mammal in need thereof by administration of VEGF-A (see [0103]) as well as teaching intratracheal administration of therapeutic compositions. Rafii does not teach administration of VEGF-A through respiratory tract.
Ruediger et al. teach methods of treating pulmonary diseases and lung injury by
the administration of VEGF (see [0018]). Ruediger et al. also teach that VEGF occurs as one of a number of different isoforms including VEGF165 and that the different isoforms are biologically active (see [0020]). Ruediger et al. disclose that the VEGF
administration should be intra-tracheal or by inhalation and this is preferred because
systemic side effects using this way of application are very unlikely to occur. It would
have been prima facie obvious to one of ordinary skill in the art before the effective filing
date of the claimed invention to practice the method of Rafii for subjects in need of promoting lung growth including subjects with pulmonary hypoplasia and administer the
VEGF of Ruediger et al., including VEGF165, via the respiratory tract or by inhalation because the tissue to which the VEGF is to target is the lung and such administration would be the most direct means for delivery of the therapeutic agent. One would have a reasonable expectation of success because Ruediger et al. teach that such routes of administration are acceptable for VEGF. Therefore, the invention as a whole would have been prima facie obvious, absent evidence to the contrary.
This is a rejection reintroduced in response to the most recent amendment to the claims. Therefore, there are no outstanding arguments directed to this ground of rejection.
Claims 1 and 10-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rafii (US Pat Pub 2013/0224161 A1) and Ruediger et al. (US Pat Pub 2006/0040860) as applied above and further in view of Yang et al (Hypertension 39(3): 815-820, 2002).
The disclosure of Rafii and Ruediger et al. is as described above. Neither Rafii nor Ruediger et al. teach methods which monitor the subject for hypotension during or after administration of the VEGF or administering one or more agents which increase blood pressure.
Yang et al. teach that VEGF induces hypotension in normotensive subjects, which is considered a major side effect when using VEGF for treatment of conditions which are not hypertensive conditions. Yang concludes that precautions may be necessary when VEGF is systemically administered.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to monitor the blood pressure of the subjects being administered VEGF in the method of Rafii because Yang et al. teach that VEGF administration induces hypotension in normotensive subjects. One of ordinary skill in the art, recognizing that VEGF can cause hypotension when being administered would further be motivated to administer a second agent to counteract the drop in blood pressure which would be expected when administering VEGF to treat improve lung function or lung injury in the method of Rafii. While the references do not suggest such an action, the use of agents to counter the side effects of VEGF would have been within the skill and knowledge of the artisan at the time the invention was made, absent evidence to the contrary. Therefore, the invention as a whole would have been prima facie obvious, absent evidence to the contrary.
This is a rejection reintroduced in response to the most recent amendment to the claims. Therefore, there are no outstanding arguments directed to this current ground of rejection. Applicant’s arguments directed to the previous 103 for claims 1 and 10-11 will be addressed below.
Response to Arguments
Applicant argues at pages 13-14 of the response that Yang et al. does not cure the deficiencies of Rafii, Ruediger, Delago-Pena, LeMahieu, and/or Carmeliet and Yang provides no teachings relevant to improving lung growth and function by administering VEGF-A as recited in claim 1. Applicant asserts that the Office Action provides no guidance on how Yang should be combined with the cited references to arrive at claim 1 as claim 1 does not involve monitoring for hypotension nor administering any other composition that is supposedly taught by Yang et al.
First, Applicant should note that when considering dependent claims, the dependent claim includes all the limitations of the claim from which it depends. Therefore, if a rejection is made over a dependent claim, it is proper to make the rejection over the dependent claim and all the claims that it depends from. Claim 1 is directed to a method “comprising” certain steps, therefore, Claim 1 does not exclude the inclusion of additional steps. Applicant argues:
Applicant also traverses the various instances of apparent Official Notice or unsupported assumptions that some claim elements are obvious while "the references do not suggest such an action." To the extent that the Office is taking Official Notice of these unsupported conclusions, Applicant disagrees with respect to these particular claim combinations and notes that any future rejection relying on these conclusions must be supported with "documentary evidence." MPEP § 2144.03 (noting that the Patent Office "must point to some concrete evidence" in order to support such a rejection).
Applicant appears to be arguing that the statement in the rejection that VEGF can cause hypotension when administered is taking official notice. Applicant’s argument has been fully considered but is not found persuasive. Yang et al. teach that VEGF administration induces hypotension in normotensive subjects. Applicant may also be taking offense to the statement “while the references do not suggest such an action”, referring to Rafii, Ruediger, LeMahieu and Carmeliet, this would not be a statement of Official Notice, but rather a statement that this was not taught in these references. Possibly Applicant is referring to the statement that “the use of agents to counter the side effects of VEGF would have been within the skill and knowledge of the artisan at the time the invention was made”. However, again, this is not Official Notice as this teaching is found in Yang et al. and one of ordinary skill in the art would more likely than not already be aware of this effect of VEGF because the side effects of VEGF are well documented, although Yang et al. was cited for this teaching.
Yang et al. was cited for the teaching that VEGF induces hypotension in normotensive subjects and that precautions may be necessary when VEGF is systemically administered medication via inhalation. This teaching is relevant to the limitations of claims 10-11 which include monitoring the subject for hypotension during administration of VEGF as well as administration of agents which would increase blood pressure. Such monitoring and treatments would be obvious in view of the teachings of Yang et al. and would be properly incorporated into the method of Rafii and Ruediger et al. Therefore, the rejection is maintained for the reasons of record.
Claims 50-51 and 53-54 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rafii (US Pat Pub 2013/0224161 A1) in view of Ruediger et al. (US Pat Pub 2006/0040860).
Rafii teach a method of inducing organ regeneration in a subject in need thereof wherein the organ is the lung by administering VEGF-A to enhance or induce organ regeneration (see [0017]. Rafii teach that lung diseases which could be treated include but are not limited to lung hypoplasia, lung trauma, pulmonary hypoplasia, lung injury, and bronchopulmonary dysplasia (see [0104]-[0105]). Rafii also teaches that the method provides for alveolarization in a mammal in need thereof by administration of VEGF-A (see [0103]). Rafii also teach compositions which are formulated for parenteral administration by injection (see [0083]). Rafii also teach that HB-EGF stimulates alveolar regeneration (see [0166]) but does not administer HB-EGF exogenously. Rafii does not teach administration of VEGF or HB-EGF via the respiratory tract.
Ruediger et al. teach methods of treating pulmonary diseases and lung injury by the administration of VEGF (see [0018]) and that the VEGF administration should be intra-tracheal or by inhalation and this is preferred because systemic side effects using this way of application are very unlikely to occur. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to practice the method of Rafii via systemic administration or administer the VEGF by the method of Ruediger et al., via inhalation administration because the tissue to which the VEGF is to target is the lung and such administration would be the most direct means for delivery of the therapeutic agent. Additionally, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to additionally administer HB-EGF in the method of Rafii, by systemic administration or via the respiratory tract because Rafii teaches that HB-EGF also stimulates alveolar regeneration and this would be beneficial for promoting lung growth in a subject. One would have a reasonable expectation of success because Rafii teach that both VEGF and HB-EGF promote lung growth and because Ruediger et al. teach that respiratory tract administration of proteins for treating lung conditions is desirable and effective. Therefore, the invention as a whole would have been prima facie obvious, absent evidence to the contrary.
This is a rejection reintroduced in response to the most recent amendment to the claims. Therefore, there are no outstanding arguments directed to this ground of rejection.
Claims 1, 5-8, 33 and 55-58 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rafii (US Pat Pub 2013/0224161 A1) in view of Ruediger et al. (US Pat Pub 2006/0040860), Delago-Pena et al. (An Pediatr. (Barc) 85: 70-76, 2016), LeMahieu et al. (US Pat Pub 2008/0066741) and Carmeliet et al. (WO2016/198121).
Rafii teach a method of inducing organ regeneration in a subject in need thereof wherein the organ is the lung by administering VEGF-A to enhance or induce organ regeneration (see [0017]. Rafii teach that lung diseases which could be treated include but are not limited to lung hypoplasia, lung trauma, pulmonary hypoplasia, lung injury, and bronchopulmonary dysplasia (see [0104]-[0105]). Rafii also teaches that the method provides for alveolarization in a mammal in need thereof by administration of VEGF-A (see [0103]). Rafii also teach compositions which are formulated for parenteral administration by injection (see [0083]). Rafii does not teach administration of VEGF by inhalation or treatment of an infant.
Carmeliet et al. teach the treatment of subjects suffering from lung hypoplasia, specifically directed to subjects with congenital diaphragmatic hernia (CDH), by the administration of VEGF-A. Carmeliet et al. administered nanodiamond particles chemically conjugated to VEGF in an experimental model of CDH wherein the VEGF was administered by intra-pulmonary delivery in utero. The prenatal intra-pulmonary delivery of VEGF induced “dramatic lung growth” (see Example 1 at page 6) as well as increased alveolar size and thinner alveolar septa. Carmeliet et al. does not teach administration of VEGF by inhalation.
Ruediger et al. teach methods of treating pulmonary diseases and lung injury by the administration of VEGF (see [0018]). Ruediger et al. also teach that VEGF occurs as one of a number of different isoforms including VEGF165 and that different isoforms are biologically active (see [0020]). Ruediger et al. disclose that the VEGF administration should be intra-tracheal or by inhalation and this is preferred because systemic side effects using this way of application are very unlikely to occur.
LeMahieu et al. teach methods of delivering medication via inhalation. The methods of LeMahieu et al. utilize positive pressure and aerosol, nebulized, or vaporized forms. The methods of LeMahieu et al. deliver the desired drugs to the respiratory system and would be considered intrapulmonary delivery.
Delgado-Pena et al. teach that pulmonary hypoplasia is a condition that affects infants and can result in high neonatal mortality and significant long-term morbidity (see abstract). Pulmonary hypoplasia is a congenital anomaly characterized by impaired growth and development of the lung parenchyma, airways and vessels.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to practice the method of Rafii and administer the VEGF of Ruediger et al., including VEGF165, through the respiratory tract by inhalation, because the tissue to which the VEGF is to target is the lung and such administration would be the most direct means for delivery of the therapeutic agent. Additionally, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to treat infants suffering from pulmonary hypoplasia or congenital diaphragmatic hernia with the method of Rafii because the patients present with impaired growth and development of the lungs as taught by Delgado-Pena et al. and because Carmeliet et al. teach the treatment of lung hypoplasia, specifically in congenital diaphragmatic hernia (CDH), by the administration of VEGF-A and that such treatment (prenatal intra-pulmonary delivery of VEGF) results in dramatic lung growth. One would have a reasonable expectation of success in practicing the method of Rafii because of the results demonstrated by Carmeliet et al. and because Ruediger et al. teach that inhalation routes of administration are acceptable for VEGF and LeMahieu et al. provide for a drug delivery system for intrapulmonary administration. Therefore, the invention as a whole would have been prima facie obvious, absent evidence to the contrary.
Response to Arguments
Applicant argues at page 7 of the response that the claimed method cannot be obvious over the cited references because the cited references do not teach the limitations of the claims and because there is not a reasonable expectation of success. Applicant asserts that Rafii does not provide any evidence that administering a VEGF to a subject would have any effect on the lung. Applicant’s argument has been fully considered, but is not found persuasive.
One of ordinary skill in the art before the effective filing date of the claimed invention would have already been aware that VEGF stimulates lung growth. This is a basic teaching and fact of the art. As pointed out previously, the prior art was already aware of the ability of VEGF to stimulate lung growth (see Sakurai et al., Am. J. Physiol. Lung Cell Mol. Physiol. 292: 1742-1747, 2007, cited by Applicant on 18 November 2020). One of ordinary skill in the art to which the invention pertains would have been aware of this teaching as is evidenced by the fact that it was cited in the IDS submitted by Applicant. Applicant has offered no reasons why Rafii would not be enabled or why one of ordinary skill in the art would not reasonably expect the method of Rafii to work in view of the prior art teaching that VEGF-A stimulates lung growth other than the lack of working examples in Rafii, which are not required.
Applicant argues at page 7 of the response that Rafii does not exemplify administration of any VEGF, including VEGF-A, as required in the present claims. Again, Applicant is arguing that Rafii does not provide a working example, which is not found persuasive as a working example is not required for Rafii to provide a teaching as outlined above. Applicant asserts that because Rafii also teaches lung regeneration by administering EGF and an antibody to MMP14, including PCECs for treatment of lung disorders, a person of ordinary skill in the art would have started with a composition comprising EGF and PCECs. Applicant’s argument has been fully considered, but is not found persuasive. A reference is good for all that it teaches and while Rafii teaches an embodiment which utilizes EGF and PCECs, Rafii also teaches a method of inducing organ regeneration in a subject in need thereof wherein the organ is the lung by administering VEGF-A to enhance or induce organ regeneration (see [0017]. The fact that Rafii teaches an additional embodiment for lung growth does not teach away from administration of VEGF-A to promote lung growth.
Applicant argues that the Office did not provide any reasoning or factual basis for asserting a motivation to combine the cited references and that the Office asserted that the combination teaches one to "administer the VEGF of Ruediger et al., including VEGF165, through the respiratory tract by inhalation, because the tissue to which the
VEGF is to target is the lung and such administration would be the most direct means for delivery of the therapeutic agent." Applicant’s arguments have been fully considered, but are not found persuasive. As pointed out above, Rafii teaches a method of lung growth by administering VEGF-A but does not teach administration through the respiratory tract or by inhalation. Ruediger et al. teach methods of treating pulmonary disease and lung injury by administration of VEGF (which is VEGF-A), including VEGF165, and further discloses that the VEGF administration should be intra-tracheal or by inhalation which is preferred because systemic side effects are reduced or unlikely to occur. Motivation for combining the references is clear from the teachings as both the references involve administration of VEGF for treating lung disease and Ruediger et al. provide for an administration route that would reduce side effects.
Applicant asserts at page 9 of the response that there is nothing in the teachings of Ruediger, Delgado-Pena, LeMahieu, and/or Carmeliet that, when combined with Rafii, teach or suggest the methods claim or motivate one to combine the cited references in any meaningful way to arrive at the claimed methods. 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).
Applicant additionally asserts that one of ordinary skill in the art would not and could not be able to draw any meaningful conclusions about the effect a composition comprising VEGF-A would have on lung growth based on the teachings of Ruediger. Again, Applicant’s argument is not persuasive in view of Applicant’s own IDS submission of Sakurai et al. which teaches that VEGF stimulates lung growth. Additionally, Reudiger was not cited for a teaching that VEGF stimulates lung growth.
At page 9 of the response, Applicant argues that Reudiger has nothing to do with promoting lung growth and that Reudiger does not disclose a composition for use in a method of promoting lung growth. Applicant’s arguments have been fully considered, but are not found persuasive. Ruediger et al. was cited for teaching methods of treating pulmonary diseases and lung injury by the administration of VEGF (see [0018]) as well as the various isoforms of VEGF which are biologically active (see [0020]) and routes of administration which include inhalation (see [0032]) and the motivation to select such routes of administration. Applicant additionally argues that “there is no guidance on how to combine the teachings of Ruediger with the lung PCEC transplantation method of Rafii”. Applicant’s argument has been fully considered, but is not found persuasive. Rafii was not cited for the teaching of lung PCEC transplantation and the rejection did not rely on such a method.
Applicant asserts that LeMahieu is directed to a device delivering any number of drugs to the respiratory system but provides no teachings relevant to improving lung growth and function by administering VEGF-A as recited by the claims. Applicant’s argument has been fully considered, but is not found persuasive. If LeMahieu had provided such teachings, the instant rejection would have been made under anticipation citing LeMahieu as the only reference required to reject the claim(s). LeMahieu was cited for the general teaching that methods of delivering medication via inhalation were known in the art before the filing date of the instant claims. Applicant argues that LeMahieu does not demonstrate that VEGF-A could be administered by inhalation with any expectation of success. Applicant’s argument has been fully considered, but is not found persuasive. The teaching of LeMahieu provides a reasonable expectation of success that one of ordinary skill in the art before the filing date of the claimed invention would be able to administer a protein, VEGF-A, via inhalation through the respiratory tract to a subject because such methods are currently used in the art today for a variety of drugs and proteins. Applicant has provided no reason to doubt the teachings of the prior art other than to argue that because there is not a working example, then there must not be any expectation of success.
Applicant argues at page 10 of the response one of ordinary skill in the art would not be able to draw any meaningful conclusions about the effect a composition comprising VEGF-A would have on lung growth based on the teachings of Delgado-Pena as VEGF-A is not mentioned at all. 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).
Applicant asserts that there is no guidance on how or why one would combine Delgado-Pena with the lung PCEC transplantation method of Rafii. Applicant is again reminded that Rafii was not cited for a teaching of lung PCEC transplantation and therefore, this argument is not relevant to the rejection which has been made above. Delgado-Pena was cited for the teaching that pulmonary hypoplasia is a condition that affects infants and can result in high neonatal mortality and significant long-term morbidity and that pulmonary hypoplasia is a congenital anomaly characterized by impaired growth and development of the lung parenchyma, airways and vessels.
Applicant asserts at page 11 of the response that the Examiner’s statement:
Carmeliet et al. teach the treatment of subjects suffering from lung hypoplasia, specifically directed to subjects with congenital diaphragmatic hernia (CDH), by the administration of VEGF-A and that such treatment (prenatal intra-pulmonary delivery of VEGF) results in dramatic lung growth
is inaccurate and that “no such teaching is present in Carmeliet” and that “Carmeliet could be considered to teach away from the presently claimed methods”.
Applicant’s arguments have been fully considered, but are not found persuasive. Example 1 of Carmeliet et al. describe improvement in lung growth in an experimental congenital diaphragmatic hernia model. The CDH model results in lung hypoplasia, therefore, the subjects of Carmeliet et al. meet the limitations of the claims as the subjects would be in need of promoting lung growth. Carmeliet et al. administered a composition comprising VEGF (which is VEGF-A (see page 5, line 20)) intratracheally and the trachea is part of the respiratory tract. Carmeliet et al. conclude that prenatal intra-pulmonary delivery of VEGF induced dramatic lung growth in their experimental model of CDH (bottom of page 6).
Applicant asserts at pages 11-12 of the response that Carmeliet et al. teach a combination therapy involving tracheal occlusion and administration of a conjugated, nanoparticle-bound VEGF and unbound VEGF did not provide a therapeutic effect. Applicant’s arguments have been fully considered, but are not found persuasive. The teachings of Carmeliet et al. cannot be viewed in a vacuum. The experiments of Carmeliet et al. were performed in a pre-clinical model of CDH in utero. When a fetus is treated in utero for CDH, tracheal occlusion is a standard therapy. One of ordinary skill in the art would understand that tracheal occlusion would not be considered appropriate for all subjects in need of lung growth. A balloon is placed in the trachea of the fetus to block lung fluid which induced lung growth. The balloon is removed around 34 weeks prior to birth. While Carmeliet did not observe a therapeutic effect when VEGF was administered in the absence of a nanoparticle, Carmeliet did speculate that “the lack of measurable effects of unconjugated VEGF suggests that gradual release – mimicking the spatial and temporal expression of VEGF in normal lung development – is a requirement for bioactivity in this experimental model” (see page 7, top of page). While there is a difference in therapeutic outcome of VEGF versus conjugated VEGF, the instant claims are directed to “a composition comprising VEGF-A” and Carmeliet clearly teach that VEGF-A promotes lung growth in a prenatal model of CDH.
Applicant argues at pages 12-13 that it has been well-established in the field that inhalation of proteins involves a number of difficulties and the Examiner appears to dismiss this fact and the work done by the inventors as simply routine. Applicant refers to the Puder Declaration (submitted February 13, 2023). Applicant has presented these arguments regarding alleged difficulties, which have been previously considered and answered as well as consideration of the Puder Declaration (see response mailed 22 May 2023). In the instant application, it is noted that Applicant did not document or overcome any difficulties in administering VEGF-A through the respiratory tract by inhalation. Applicant asserts that changing the route of administration of a composition is not as easy as the Examiner would suggest and one of ordinary skill in the art would understand that such considerations would require extensive experimentation with a low probability of success. Applicant’s arguments have been fully considered, but are not found persuasive.
Rafii teaches administration of VEGF-A to stimulate lung growth and administration would be useful for treating lung conditions as well as the prior art teaching that VEGF-A was known to stimulate lung growth. Carmeliet et al. specifically teach treating pulmonary hypoplasia and congenital diaphragmatic hernia in utero by administering VEGF-A directly into the lung. Ruediger et al teach that pulmonary diseases and lung injury could be treated by administration of VEGF, including by inhalation, which is a preferred route due to a reduction of systemic side-effects. While the prior art was aware that delivery of drugs and proteins via inhalation posed difficulties, the presence of difficulties does not necessarily equate to unpredictability or a lack of a reasonable expectation of success. See Agu et al. (Respir. Res. 2: 198-209, 2001; cited in Office action mailed 22 May 2023). While different techniques may be necessary to administer a protein via the lung, the art was aware of such obstacles and such are not a barrier to administration as it would have been within the skill of an artisan in the field to determine the means for administering the protein such that it could be delivered via the lung. As in the instant application, administration of VEGF via inhalation did not require any special modification of the VEGF in order for it to be administered or have a biological effect on the lung. Therefore, while the prior art acknowledges that there might be difficulties with administration of a compound via the lungs, clearly these difficulties do not equate to "no expectation" of success in administration and biological effects being realized. Agu et al. teach that various macromolecules have been administered via the lungs and that systemic responses were obtained, including administration of immunoglobulins, CsA, G-CSF and interferons. The molecular weight of VEGF is similar to interferon and therefore, one would reasonably expect that VEGF could be administered with systemic responses. Additionally, McGillick et al. (J. Physiol. 594(5): 1399-1420, 2016; cited previously in Office action mailed 22 May 2023) teach that intratracheal VEGF administration in the fetus results in fetal lung maturation and lung growth, which clearly provides evidence that the VEGF administered into the lungs crosses the alveolar barrier to provide systemic effects.
Claims 50-54, 59-60 and 67-68 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rafii (US Pat Pub 2013/0224161 A1) in view of Ruediger et al. (US Pat Pub 2006/0040860), Delago-Pena et al. (An Pediatr. (Barc) 85: 70-76, 2016), LeMahieu et al. (US Pat Pub 2008/0066741) and Carmeliet et al. (WO2016/198121).
Rafii teach a method of inducing organ regeneration in a subject in need thereof wherein the organ is the lung by administering VEGF-A to enhance or induce organ regeneration (see [0017]. Rafii teach that lung diseases which could be treated include but are not limited to lung hypoplasia, lung trauma, pulmonary hypoplasia, lung injury, and bronchopulmonary dysplasia (see [0104]-[0105]). Rafii also teaches that the method provides for alveolarization in a mammal in need thereof by administration of VEGF-A (see [0103]). Rafii also teach compositions which are formulated for parenteral administration by injection (see [0083]). Rafii also teach that HB-EGF stimulates alveolar regeneration (see [0166]) but does not administer HB-EGF exogenously. Rafii does not teach administration of VEGF or HB-EGF via the respiratory tract.
Carmeliet et al. teach the treatment of conditions suffering from lung hypoplasia, specifically directed to subjects with congenital diaphragmatic hernia (CDH), by the administration of VEGF-A. Carmeliet et al. administered nanodiamond particles chemically conjugated to VEGF in an experimental model of CDH wherein the VEGF was administered by intra-pulmonary delivery in utero. The prenatal intra-pulmonary delivery of VEGF induced “dramatic lung growth” (see Example 1 at page 6) as well as increased alveolar size and thinner alveolar septa. Carmeliet et al. does not teach administration of VEGF by inhalation.
Ruediger et al. teach methods of treating pulmonary diseases and lung injury by the administration of VEGF (see [0018]) and that the VEGF administration should be intra-tracheal or by inhalation and this is preferred because systemic side effects using this way of application are very unlikely to occur.
Delgado-Pena et al. teach that pulmonary hypoplasia is a condition that affects infants and can result in high neonatal mortality and significant long-term morbidity (see abstract). Pulmonary hypoplasia is a congenital anomaly characterized by impaired growth and development of the lung parenchyma, airways and vessels.
LeMahieu et al. teach methods of delivering medication via inhalation. The methods of LeMahieu et al. utilize positive pressure and aerosol, nebulized, or vaporized forms. The methods of LeMahieu et al. deliver the desired drugs to the respiratory system and would be considered intrapulmonary delivery. LeMahieu et al. teach a number of different drugs which would be suitable for the method including VEGF (see page 22, column 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to practice the method of Rafii via systemic administration or administer the VEGF by the method of Ruediger et al. (who teaches VEGF165), via inhalation administration because the tissue to which the VEGF is to target is the lung and such administration would be the most direct means for delivery of the therapeutic agent. Additionally, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to treat infants suffering from pulmonary hypoplasia with the method of Rafii because the patients present with impaired growth and development of the lungs as taught by Delgado-Pena and because Carmeliet et al. teach the treatment of lung hypoplasia, specifically in congenital diaphragmatic hernia (CDH), by the administration of VEGF-A and that such treatment (prenatal intra-pulmonary delivery of VEGF) results in dramatic lung growth.. Furthermore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to additionally administer HB-EGF in the method of Rafii, by systemic administration or via the respiratory tract because Rafii teaches that HB-EGF also stimulates alveolar regeneration and this would be beneficial for promoting lung growth in a subject. One would have a reasonable expectation of success because Rafii teaches that both VEGF and HB-EGF promote lung growth, Carmeliet et al. teach that VEGF administration results in lung growth and because Ruediger et al. teach that respiratory tract administration of proteins for treating lung conditions is desirable and effective and LeMahieu et al. teach that means for administration via inhalation are known and that VEGF could be administered via inhalation. Therefore, the invention as a whole would have been prima facie obvious, absent evidence to the contrary.
Response to Arguments
Applicant argues at page 17 of the response that one of ordinary skill in the art would not and could not have arrived at the method of claim 50 with any expectation of success in view of the references cited in the grounds of rejection.
Applicant’s arguments have been fully considered but are not found persuasive. With regard to expectation of success, the prior art of Rafii, Ruediger and Cameliet et al. suggest otherwise and indicate that VEGF-A stimulates lung growth, teach intrapulmonary administration of VEGF-A, including by inhalation, and for the treatment of pulmonary hypoplasia and CDH. While there is not a single reference that includes all the limitations of the claims, the various aspects of the claims are contained in multiple references and it would have been prima facie obvious to combine the teachings as stated above to arrive at the claimed invention with an expectation of success for the reasons provided.
Conclusion
No claim is 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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/Christine J Saoud/Primary Examiner, Art Unit 1645