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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 6 October, 2022 was filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Priority
This application is a 371 of PCT/AU2021/050321 04/08/2021.
Status of the Application
Claims 1, and 30-48 are pending. Claims 2-29 have been cancelled. Claim 1 is currently amended. Claims 1 and 30-48 are currently under examination.
Claim Objections
Claim 41 is objected to because of the following informalities: there are two period marks at the end of claim 41. Appropriate correction is required.
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 1 and 30-48, are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating systemic infection in a subject, does not reasonably provide enablement for prevention of said disease or disorder. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." In In re Wands, 8 USPQ2d 1400 (1988), the factors to be considered in determining whether a disclosure meets the enablement requirement are as follows:
1. The nature of the invention
2. The state of the prior art
3. The predictability or lack thereof in the art
4. The amount of direction or guidance present
5. The presence or absence of working examples
6. The breadth of the claims
7. The quantity of experimentation needed, and
8. The level of skill in the art
The Nature of the Invention and Breadth of the Claims
Claims 1 and 41 are drawn to a method for treating or preventing a condition, and/or
symptom or clinical manifestation, associated with systemic infection in a subject, comprising intravenously administering to the subject ascorbic acid. The nature of the invention is therefore drawn to the pharmaceutical art. These claims cover diseases that are known to exist and those that may be discovered in the future, for which there is no enablement provided.
The State of the Prior Art and the Predictability or lack thereof in the art
The state of the prior art is that the pharmacological art involves screening in vitro and in vivo to determine which compounds exhibit the desired pharmacological activities (i.e. what compounds can treat which specific disease by what mechanism). There is no absolute predictability even in view of the seemingly high level of skill in the art. The existence of these
obstacles establishes that the contemporary knowledge in the art would prevent one of ordinary skill in the art from accepting any therapeutic, curative, or preventative regimen on its face.
While a full discussion of each disease which is encompasses by Applicant's claim
language will not be given; the following examples teach that the state of the prior art
with respect to the claimed diseases has not advanced to the point of being predictive
of the curative treatment of the breadth of diseases instantly claimed.
"Treatment" is defined in the present specification as follows [0040]:
“As used herein the terms "treating", "treatment", "preventing", "prevention" and
grammatical equivalents refer to any and all uses which remedy, prevent, retard or delay the
establishment of a condition, symptom or clinical manifestation associated with a system
infection or sepsis, or otherwise prevent, hinder, retard, or reverse the progression of such a
condition, symptom or clinical manifestation. Thus, the terms "treating" and ''preventing" and
the like are to be considered in their broadest context. For example, treatment does not
necessarily imply that a patient is treated until total recovery. For example, where a condition
displays or is characterized by multiple symptoms or manifestations, the treatment or prevention
need not necessarily remedy, prevent, hinder, retard, or reverse all of said symptoms or
manifestations, but may prevent, hinder, retard, or reverse one or more of said symptoms or
manifestations.”
The current state of the art is that that full scope of diseases claimed within instant
claims is not curative. The full scope of diseases are not curable or preventable.
For example, systemic infection:
A systemic infection is not a single disease, or cluster of closely related disorders. There are many types of systemic infection which have in common a spread of harmful pathogens, such as bacteria or viruses, throughout the body via the bloodstream. They can occur in pretty much every part of the body. Here are some assorted categories a systemic infection:
Pneumonia is an infection that inflames the air sacs in one or both lungs, which may fill with fluid or pus. Common symptoms include cough with phlegm or pus, fever, chills, and difficulty breathing. Pneumonia can be caused by bacteria, viruses, or fungi, and the severity of the condition can vary. Treatment typically depends on the underlying cause and may include antibiotics for bacterial pneumonia.
Meningitis is an infection and swelling, called inflammation, of the fluid and membranes around the brain and spinal cord. These membranes are called meninges. The inflammation from meningitis most often triggers symptoms such as headache, fever and a stiff neck. Viral infections are the most common cause of meningitis in the United States. Bacteria, parasites and fungi also can cause it. Sometimes meningitis improves in a few weeks without treatment. But meningitis also can cause death. It often needs quick treatment with antibiotics.
Chlamydia can ascend to the uterus in women and cause scarring, it can also cause scarring of the male reproductive tract and subsequent infertility if not treated with antibiotics. It affects a variety of sites, including the eyes and the rectum. For example, the systemic disease lymphogranuloma venereum (LGV) is caused by a type of chlamydia that spreads throughout the body.
The flu (influenza) is a viral respiratory illness that causes fever, chills, runny nose, body aches, and cough. It spreads easily from person to person. The flu can cause moderate to severe symptoms. Most people recover fully. Children, older adults, and people with certain health conditions are at risk for severe illness and even death.
Necrotizing fasciitis, commonly known as flesh-eating disease, is a serious bacterial infection that affects the tissue under the skin called fascia. It can develop rapidly and is characterized by symptoms such as severe pain, swelling, fever, and changes in skin color (red, purple, or black). This condition requires immediate medical attention, including antibiotics and surgery to remove damaged tissue. The most commonly affected areas are the limbs and perineum.
Snake Envenomation, snake venoms can be classified as hemotoxic (attacking tissue and blood) and neurotoxic (damaging or destroying nerve tissue). The venom consists of proteins, polypeptides, and enzymes that cause necrosis and hemolysis. Pit viper bites classically appear as two fang punctures (one or three puncture wounds occur, but rarely) with local swelling and necrosis. Extremity bites are rarely complicated by infection and compartment syndrome, and prophylactic fasciotomies often do more harm than good. Clinical effects of snakebites range from mild local reactions to life-threatening systemic reactions, depending on the species and size of the snake involved; the location of the bite(s); the volume of venom injected; and the age, size, and health of the victim. Children are more likely to suffer significant morbidity and mortality because they receive a larger envenomation relative to body size.
The existence of these obstacles establishes that the contemporary knowledge in the art
would prevent one of ordinary skill in the art from accepting any therapeutic, curative, or
preventative regimen on its face.
The Amount of Guidance Present and Presence/Absence of Working Examples
The only guidance disclosed by the specification regarding prevention of a condition and/or symptom or clinical manifestation associated with systemic infection in a subject is found on page 2 of the specification with variations found on pages 3-5.
“[I]intravenously administering to the subject ascorbic acid or a pharmaceutically acceptable salt, ester or isomer thereof in an amount of between about 700 mg/kg body weight and about 4,000 mg/kg body weight per day.”
The specification does not provide any guidance for determining which particular patient population would be susceptible to developing a systemic infection. Also lacking are data showing that the compounds are capable of treating all or every septic infection.
The quantity of experimentation needed, and level of skill in the art
In order to treat every or all systemic infection types one would need to precisely identify those subjects with the disease or disorder who are likely to respond to treatment, administer the claimed invention, and demonstrate that administration directly resulted in the subject overcoming the disease or disorder. One skilled in the art would conclude that the guidance in the specification would not have taught one skilled in the art how to treat every or all cancer types using the compounds of formula (I), because there is no guidance for how to select a patient population and no evidence that the claimed compound can broadly treat every systemic infection type. Given the lack of guidance in the specification and the lack of success in the prior art, one skilled in the art would find that preventing the claimed diseases or disorders would require experimentation that is unduly burdensome. This rejection may be overcome by cancelling claims 1 and 41, or specifying which condition, and/or symptom or clinical manifestation, associated with systemic infection type is being treated from line 1-2 of claim 1 and 41.
Claim Rejections - 35 USC § 112
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.
Claims 1 and 30-48 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 1 and 41, the term “associated” in claim 1 line 2 and claim 41, line 2 is a relative term which renders the claim indefinite. The term “associated” 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.
Claims 1 and 41 requires more clarification as to what the applicant means as a condition, and/or symptom or clinical manifestation, associated with systemic infection in a subject. Neither the claims nor the specification provide additional information of what the condition, and/or symptom or clinical manifestation associated with systemic infection in claims 1 and 41 are. For example fatigue is a condition associated with a systemic infection but is not addressed in the specification. Furthermore, a relative providing care for a loved one with a condition, symptom, clinical manifestation from a systemic infection in a subject whose health is deteriorating could also experience clinical depression from the trauma of providing care or loss of the loved one which could also be associated to a condition, symptom, clinical manifestation from a systemic infection with claims 1 and 41 as written.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1 and 30-48 are rejected under 35 U.S.C. 103 as being unpatentable over Jamison (WO 2012/012370 Al) in view of Lykkesfeldt (The Pharmacokinetics of Vitamin C) and further in view of Cheng (Successful High-Dose Vitamin C Treatment of Patients with Serious and Critical COVID-19 Infection).
The instant claims are directed to a method of treating a condition, and/or symptom or clinical manifestation, associated with systemic infection in a subject, comprising intravenously administering to the subject 2000 to about 4,000 mg/kg body weight per day of ascorbic acid two or more times a day.
Jamison et al. teach treating proliferative, infectious bacterial, viral and fungal infections and sepsis [00146]. Jamison an embodiment in which a cardio vascular disorder is hypotension [00149]. Jamison teaches vitamin C as used in the methods provided can be delivered as a single bolus dose [00182]. Jamison discloses embodiments in which vitamin C is administered over time in a continuous infusion or as bolus doses [00189]. Jamison also teaches an embodiment in which vitamin C is administered intravenously [00202]. Jamison also discloses embodiments in which the vitamin C is administered in a dose range of 500-200,000 mg a day [00196]. Jamison also discloses embodiments in which vitamin C is administered 1-20 times a day and that the administration can be continuous or intermittent and administered every 1-10 hours [00191]. Jamison teaches an embodiment in which the vitamin C combination regimen is administered over a period of time of 1 day to 50 years [00220]. Jamison teaches that a combination therapy includes A first therapy of a prophylactic or therapeutic agent such as vitamin C which is administered prior to the administration of a second therapy[00222]. Jamison teaches in example 8, an injectable formulation of a vitamin C wherein sodium ascorbate is used [00250].
However, Jamison et al. fail to explicitly disclose a therapy in which a first bolus infusion is administered with a second subsequent continuous infusion in a therapy and a specific treatment for SARS-CoV-2, also known as COVID-19 coronavirus.
Lykkesfeldt et al. teach an increased dosage requirement of vitamin C during sepsis “[a]n obvious display of increased vit C turnover in critical illness is that large doses are often needed to replete the individual to the level of a healthy control. These doses exceed those necessary to saturate a healthy individual by many-fold. One current example is sepsis patients where systemic inflammation and oxidative stress presumably increases the expenditure of vit C” (pg. 13, para. 2).
Cheng teach a method of treating COVID-19 patients with an intravenous dose of 10,000-20,000 mg of vitamin C for 7-10 days and an intravenous bolus of 50,000 mg vitamin C over a period of 4 hours.
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the claimed invention, to administer vitamin C in a bolus dose, followed by a continuous infusion to treat a subject with a systemic infection as taught by Jamison, Lykkesfeldt and Cheng because combining a bolus dose to replenish low vitamin C in the body with a continuous dose to maintain vitamin C concentration in the body exhibits beneficial therapeutic effects to a subject with a condition, and/or symptom or clinical manifestation, associated with systemic infection.
A person of ordinary skill in the art would have been motivated to administer a first bolus infusion of vitamin C followed by a secondary continuous infusion in a therapy for treating a systemic condition. Therefore, it is considered that the skilled person, knowing that high doses of vitamin C are needed during critical illness, such as sepsis, would optimize the administered dose to a subject with a systemic infection or condition having a full expectation of success to provide the instantly claimed methods. Therefore the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references based on the current record.
Conclusion
All claims are rejected, no claims are allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNESTO VALLE JR whose telephone number is (703)756-5356. The examiner can normally be reached 0730-1700 M-F EST, 1st Friday off.
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/E.V./Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623