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 .
Reopening of Prosecution
In view of the appeal brief filed on October 2025, PROSECUTION IS HEREBY REOPENED. New grounds of rejection are set forth below.
To avoid abandonment of the application, appellant must exercise one of the following two options:
(1) file a reply under 37 CFR 1.111 (if this Office action is non-final) or a reply under 37 CFR 1.113 (if this Office action is final); or,
(2) initiate a new appeal by filing a notice of appeal under 37 CFR 41.31 followed by an appeal brief under 37 CFR 41.37. The previously paid notice of appeal fee and appeal brief fee can be applied to the new appeal. If, however, the appeal fees set forth in 37 CFR 41.20 have been increased since they were previously paid, then appellant must pay the difference between the increased fees and the amount previously paid.
A Supervisory Patent Examiner (SPE) has approved of reopening prosecution by signing below.
Status of Application
Applicants' Appeal Brief filed 10/09/2025 is acknowledged. Claims 1-5, 8-9, and 11 are currently pending and are examined on the merits within.
New and Modified Rejections
Claim Rejections – 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 2-4 and 11 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 the treatment of heterotopic ossification, myositis ossificans, myositis ossificans, vascular calcification, or pathologic calcification does not reasonably provide enablement for preventing these ossifications or calcifications. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to prevent these ossifications or calcifications the invention commensurate in scope with these claims.
The factors that may be considered in determining whether a disclosure would require
undue experimentation, are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
1) the quantity of experimentation necessary,
2) the amount of direction or guidance provided,
3) the presence or absence of working examples,
4) the nature of the invention,
5) the state of the prior art,
6) the relative skill of those in the art,
7) the predictability of the art, and
8) the breadth of the claims.
These factors are always applied against the background understanding that scope of
enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
Evidence suggests arsenic trioxide (ATO) has potential, specifically as a Hedgehog (Hh) signaling pathway inhibitor, to suppress heterotopic ossification (HO). (Bei et al. Heterotopic ossification: Current developments and emerging potential therapies. Chin Med J (Engl). 2025 Jan 17;138(4):389–404). However, there is no direct, established clinical evidence that Arsenic Trioxide (ATO) is used for the prevention of Heterotopic Ossification (HO) and evidence regarding vitamin D or cholecalciferol (Vitamin) for preventing heterotopic ossification (HO) is conflicting and limited.
The invention also recites that it provides a method to prevent or to treat a disease or condition as defined herein in a subject, which method comprises administering to said subject an effective amount of a dry powder pharmaceutical composition as defined herein. The invention is described in more detail by the following Examples. (pg. 4, lines 10-18, pg. 6 lines 13-21, pg. 33 lines 8-18).
The claims at issue are drawn to pharmaceutical formulations that have the function of treating or preventing a disease or disorder in a subject in need thereof. The pharmaceutical was composed of an inclusion complex comprising: a targeted carrier comprising an inclusion host and having a targeting moiety attached thereto, and an active agent or precursor thereof non-covalently associated with the inclusion host. The claims also recite treating or preventing a diseases or disorders by administering the inclusion complex in an effective amount to a subject in need thereof. These products and methods require the ability to treat all disease and disorder with an active agent complexed in the inclusion complex as well as to prevent and eliminate all risk of all disease and disorder with an active agent complexed in the inclusion complex.
All diseases and disorders are not able to be prevented with an active agent. For example, great efforts have been made to slow the progression of or reduce the intensity of Alzheimer’s disease, however there is no agent that is known to be able to prevent the condition (see Selkoe Science 2012 337:1488-1492). Similarly, all cancers cannot be prevented (see www.cancer.org/treatment/treatments-and-side-effects/complementary-and-alternative-medicine/learning-about-new-cancer-prevention-methods/intro.html; 2014). Because of the known unpredictability of the art, and in the absence of experimental evidence, no one skilled in the art would accept the assertion that the instantly claimed products could be made and methods could be practiced commensurate in scope with the claims. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Specifically, the applicants provide different Formulating Drugs, (pg. 31, line 19), Dosage (pg. 33, line 5, Potential of Synergism for Combinations of Drugs (pg. 33, line 25, and then Treatment Methods (pg. 34, line 18), but there is not Prevention Methods.
For the above reasons, prevention is not enabled.
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.
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 non-obviousness.
Claims 1-5, 8-9 and 11 are rejected under 35 USC 103 as being unpatentable over Regard et al. (US 2014/0220154 A1) and Majeti et al. (US 20180042962), in view of Huang et al. (US 20150037436 A1) and Jin et al. (Jin et al., Insulin delivery systems combined with microneedle technology. Advanced Drug Delivery Reviews 127 (2018) 119–137).
Claims 1, 9 and 11,
Regard et al. teach a method of inhibiting formation of heterotopic ossification comprising administering an antagonist of the Hedgehog pathway, (0010) and a method of preventing or treating pathologic heterotopic ossification comprising administering a drug, wherein the drug arsenic trioxide (ATO), is an antagonist of the Hedgehog (Hh) pathway (Abs). Antagonists of the Hedgehog pathway is applied to treat heterotopic ossification, vascular calcification, or pathologic mineralization. (0002).
Regard et al. do not teach vitamin D, cholecalciferol nor vitamin D analog.
Majeti et al. teach the appropriate dose of vitamin D or its derivatives to exert protective actions against vascular calcification would be in the physiological range, whereas high pharmacological doses might promote the vascular mineralization process. The guidelines for vitamin D intake vary in different countries. In the United States the recommended dietary allowances (RDA) of vitamin D are 600 IU/day (15 μg/day for ages 1-70 years, 800 (20
μg/day) for ages 71+ years and 400 IU/day for infants 0-12 months. (0106).
Huang et al. teach tissue-derived implant materials replicate the biological and mechanical function of naturally occurring extra cellular matrix, which provide the necessary support on which cells can adhere to, migrate and expand and allow the influx and efflux of cells, such as stem cells and progenitor cells, and induce and support growth and tissue repair. (0323), for localized delivery of therapeutic agents for inhibiting osteogenesis in mesenchymal stem cells in patients. The shaped acellular tissue is formed by slurry, paste, or gel, or a sponge-like shaped acellular tissue into a different shape, using three-dimensional (3D) printing to deposit a flowable slurry, paste, or gel into a three-dimensional shape. (0470). Some embodiments, the shaped acellular tissues are provided with substances for controlled-release nanotubes/nanoparticles that preferentially secrete factors for specific processes. (0471). The term “contact” refers to a state or condition of touching or of immediate or local proximity. Contacting a composition to a target destination may occur by any means of administration. (0356). The term “growth-inductive matrix” as used herein refers to a matrix containing a substance or substances capable of recruiting or stimulating local tissue genic cells so that the cells are induced (meaning to cause, bring about, bring about, or trigger) to differentiate and/or produce a tissue (0387). The term “osteoinductive matrix” as used herein refers to a matrix containing a substance or substances that recruit local cells to induce (meaning to cause, bring about, bring about, or trigger) local cells to produce bone. (0422).
Jin et al. teach microneedle (MN) had been used to efficiently deliver drugs through transdermal route (pg. 121, left col., 2nd last par. and Table 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to a method of inhibiting formation of heterotopic ossification comprising administering an antagonist of the Hedgehog pathway, comprising administering a drug, wherein the drug arsenic trioxide (ATO), and to treat heterotopic ossification, vascular calcification, or pathologic mineralization, taught by Regard et al, and to combine with vitamin D taught by, Majeti et al, Krempin et al. and to apply implant method for inhibiting locally osteogenesis in mesenchymal stem cells in a patient, taught by Huang et al. and Jin et al. since ATO is known to inhibit vascular calcification from Regard et al. and vitamin D is taught to be useful for the same purpose by Majeti et al., therefore, it would have been obvious for one with ordinary skills in the art to combine the two with the expectation that the combination would work better than either ingredient alone.
With regard to claim 2, Regard et al. teach method of treating pathologic heterotopic ossification (HO) (Title, 0002). HO presents rarely as a hereditary disorder, and is sometimes associated with lower motor neuron disorders. More commonly it is associated with spinal cord injury, trauma and brain injuries, burns, fractures, muscle contusion, and joint arthroplasty. HO is a severe complication of hip Surgery, acetabular and elbow fracture Surgery. It may occur in patients who are on neuromuscular blockade to manage adult respiratory distress syndrome, and in patients with non-traumatic myelopathies. Following combat-related trauma, for example amputation, HO is a frequent occurrence and a common problem. (0004).
With regard to claim 3, Regard et al. teach method of treating pathologic heterotopic ossification (Title) including genetic diseases fibrodysplasia ossificans progressive (FOP) and progressive osseous heterplasia (POH) the most severe manifestations of heterotopic bone formation. FOP occurs rarely and is a result of a mutation in ACVR1, which encodes a bone morphogenetic protein type I receptor. Patients with POH have inactivating mutations of the GNAS gene, which also can give rise to Albright’s hereditary osteodystrophy (AHO) when the mutations are inherited from the mother. (0030). Myositis ossifican circumscripta is characterized by the intramuscular proliferation of fibroblasts, new bone, and/or cartilage. (0031).
With regard to claim 4, Regard et al. teach method of treating pathologic heterotopic ossification (Title) with Arsenci Trioxide (ATO), in vivo, in mice (example 9, pg. 11), (example 10, pg. 11). It would be obvious the treatments can be applied to larger animals like cat or dog.
With regard to claim 5,
Regard et al. teach Hedgehog (Hh) antagonist of ATO and doses will range from 0.01 mg/kg to 100 mg/kg will be injected daily or every other day. (0097). To converse to human dose from mice, divide animal dose by 12.3: 0.0008-8.2 mg/Kg/day or for a 60 kg patient the dose range is: 0.05-487 mg/day. (Nair et al., A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. March 2016-May 2016; 7(2): 27–31).
Majeti et al. teach vitamin D doses based on the dietary allowances are 400-800 IU/day. (0105).
With regard to claim 8, Regard et al. teach ATO, which is Hedgehog (Hh) antagonist, and doses will range from 0.01 mg/kg to 100mg/kg will be injected daily or every other day. (0097). The doses are to converse to human dose from mice by dividing animal dose by 12.3 to become 0.0008-8.2mg/Kg/day.
Response to Arguments
Rejection of Claims 1-5, 8, 9, and 11 under 35 U.S.C. § 103
Applicant argues that The Combination of References Lacks a "Rational Underpinning." There is only one "articulated reasoning" for the combination of references and there is no proper or rational underpinning for the combination. First, there is absolutely no reasoning to explain why the specific techniques of Huang et al. and Jin et al. would be applied here. Second, the teachings of Majeti et al. on the subject of Vitamin D1 are far more complex than the Examiner would have them be. Third, from the teachings of these references, Appellant respectfully submits that one of ordinary skill in the art would not necessarily have a reasonable expectation that the combination would work better than ATO or Vitamin D alone.
Applicant's arguments have been fully considered but they are not persuasive because the basis for 103 rejection is that no one reference has to teach all the claim limitations for an obviousness rejection and therefore several references are combined to render the claims obvious. One with ordinary skill in the art can learn from and select specific parts of several prior arts’ teachings before the effective filing date of the invention to achieve better outcome results even though some prior arts may teach more and may teach different things. Each prior art teaches some limitations in the claims. Huang and Jin teach different drug delivery systems applicant recited in claim 1, in which Huang teaches drug delivery systems working for an acellular soft tissue-derived matrix; Exogenous tissuegenic cells and other biologically-active factors may be added to the acellular matrix. The acellular matrix may be provided as particles, a slurry, a paste, a gel, or in some other form. The acellular matrix may be provided as a three-dimensional scaffold that has been reconstituted from particles of the three-dimensional tissue. The three-dimensional scaffold may have the shape of an anatomical feature and serve as a template for tissue repair or replacement. (Abs). They work “in the body”, “void volume”, “resection pocket”, “excavation”, “injection site”, “deposition site' or “implant site' as used herein are meant to include all tissues of the body without limit, and may refer to spaces formed therein from injections, surgical incisions, tumor or tissue removal, tissue injuries, abscess formation, or any other similar cavity, space, or pocket formed thus by action of clinical assessment, treatment or physiologic response to disease or pathology as non-limiting examples thereof (0395); they work for 2.2. Bone (Osseous) Tissue Compartment (0150); Components of Bone (0161); Bone Cells (0165); Osteoblasts are specialized, mesenchymal-derived cells (0173); locally (0358); and Jin also teaches well designed to achieve low resistance, high structural strength, large area of drug exposure to the tissue and low risk of clogging (pg. 129, left col., 2nd par.). Because these techniques work in the applicant context, so they are expected to be working here. Secondly, some prior arts may teach more and may teach different things. Majeti teaches the complexity of vitamin D, as mentioned in the final rejection that it can be positive or negative regulator of VC; but the appropriate dose of vitamin D or its derivatives to exert protective actions against vascular calcification would be in the physiological range, whereas high pharmacological doses might promote the vascular mineralization process. Please see the Non-Final modified rejection above. One with ordinary skill in the art can learn from and select specific parts of several prior arts’ teachings before the effective filing date of the invention to achieve better outcome results even though some prior arts may teach more and may teach different things.
Applicant argues the question whether one of ordinary skill in the art would have had a
reasonable expectation that a combination of ATO and Vitamin D would work better than either
ingredient alone.
Applicant's arguments have been fully considered but they are not persuasive because if two ingredients are working, as explain in the rejection above, then the combination would be expected to work. When the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. Once such a reference is found, the burden is on applicant to rebut the presumption of operability. In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980). See also MPEP § 716.07. See also In re Antor Media Corp., 689 F.3d 1282, 103 USPQ2d 1555 (Fed. Cir. 2012). Specifically, in In re Antor Media Corp., the court stated:
Applicant argues that appellant can find no reasoning, other than pure impermissible hindsight. Examiner offers to support the rejection-the statement on page 6-fails to explain precisely or sufficiently why or how one of ordinary skill in the art would turn to two of the five applied references, Huang et al. and Jin et al.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Please see the reasons explained above.
Applicant argues that Krempin et al. is not analogous prior art.
Applicant's arguments have been fully considered and they are persuasive since Vitamin D has complicated effects on vascular calcification, osteogenesis, and ossification taught by Majeti (recited in the patent, recited in previous office action, and is removed from this office action to be clear), so adding Krempin is no longer relied on in this office action.
Applicant argues that Huang et al. and Jin et al. Cannot Rescue the Rejection.
Applicant's arguments have been fully considered but they are not persuasive because the basis for 103 rejection is that no one reference has to teach all the claim limitations for an obviousness rejection and therefore several references are combined to render the claims obvious. One with ordinary skill in the art can learn from and select specific parts of several prior arts’ teachings before the effective filing date of the invention to achieve better outcome results even though some prior arts may teach more and may teach different things. Each prior art teaches some limitations in the claims. Huang and Jin teach different drug delivery systems applicant recited in claim 1, in which applicant does not provide reasoning to explain why the specific techniques, as limitations in the claims, unless applicant provides reasoning to explain why the specific techniques would be applied, then prior art(s), and probably more prior art(s) would be added to reject the claim. Secondly, some prior arts may teach more and may teach different things. Also as explained above Huang and Jin teach different limitations of claim 1, in addition to Regard and Majeti and they don’t rescue Regard and Majeti.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NGOC-ANH THI NGUYEN whose telephone number is (571)270-0867. The examiner can normally be reached Monday - Friday 8:00 am.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert A Wax can be reached at 571-272-0623. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NGOC-ANH THI NGUYEN/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615