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 .
Priority
This application is a 371 of PCT/CN2022/083261 filed on 03/28/2022, which claims priority to Foreign Chinese Application No. 202110364689.6, filed on 04/02/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/04/2024 has been considered by the examiner.
Status Of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on March 02, 2026. Claims 1-19 are pending and under examination.
Specification
The disclosure is also objected to because of the following informalities: the compound of structurally formula PQQ on the backgrouwn section and the formulas on page 3 of the specification are blurred/faded to the extent that its structure is not clearly discernible. This lack of clarity could lead to ambiguity in interpreting the scope of the disclosure. Appropriate correction is required.
Free of the art
A search for the compound of the formula (I) did not identify any prior art. The closest prior art is Zhong et al (US2011/0313164A1).
Zhong teaches
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wherein R1, R2 and R3, is individually selected from hydrogen, ammonium ion (NH3), potassium, sodium, magnesium, calcium, zinc ion and lithium ion, and at least one of the three is lithium ion. However, Zhong does not teach the claimed compound
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. The difference between the claimed compound that of Zhong lies in R1 because R1 of the prior art cannot be COOR1. Therefore, the claimed compound formula (I) is novel and nonobvious.
Drawings
The drawings are objected to because the drawings provided is not sufficiently clear for examination purposes. Specifically, the images appear blurred, and the text or labels are cluttered, making it difficult to discern the elements and their details. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 1-3 and 5-20 are objected to because of the following informalities:
Claims 1 and 2 recite “compound of a formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, solvent compound or prodrug thereof.” It should read “compound of a formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, solvent compound, or prodrug thereof.”
Claim 3 as currently presented lists multiple compounds without clear separation. To ensure clarity and proper enumeration, each compound in the list should be separated by a comma, and the final item should be preceded by “and.” Additionally, ensure that there is a space between each compound structure/name for readability.
Claim 3 also recites “compounds or a pharmaceutically acceptable salts, esters, stereoisomers, solvent compounds or prodrugs thereof shown as follow...” is intended to cover a single compound of a single salt, ester, or prodrug at a time, but it uses plural language. Applicant is advised the language to say “a compound, a pharmaceutically acceptable salt, ester, stereoisomer, solvent compound, or prodrug thereof…” to align the scope with what’s actually supported and intended.
Claim 5 recites “the compound of formula (I) or pharmaceutically acceptable salts, esters, stereoisomers, solvent compounds or prodrugs thereof.” First, the plural language-salts, esters, stereoisomers, solvent compounds, or prodrugs-is unclear, as it suggests multiple forms simultaneously. The claims should be clarified to indicate whether it covers a single salt, ester, stereoisomer, or prodrug at a time. Second, a comma is needed after “compound of formula (I), solvent compound to clearly separate it from the alternative forms.
Claims 6-9 recite “The compound or a pharmaceutically acceptable salt, ester, stereoisomer, solvent compound or prodrug thereof according to claim 1.” It should read “The compound, or a pharmaceutically acceptable salt, ester, stereoisomer, solvent compound, or prodrug thereof according to claim 1,.”
Claims 10-12 recite “The compound or a pharmaceutically acceptable salt, ester, stereoisomer, solvent compound or prodrug thereof according to claim 1,” It should read “The compound, or a pharmaceutically acceptable salt, ester, stereoisomer, solvent compound, or prodrug thereof according to claim 1.”
Claims 13-16 recite “the compounds or pharmaceutically acceptable salts, esters, stereoisomers, solvent compounds or prodrugs thereof according to claim 3.” First, the plural language-compounds, salts, esters, stereoisomers, solvent compounds, or prodrugs-is unclear, as it suggests multiple forms simultaneously. The claims should be clarified to indicate whether it covers a single salt, ester, stereoisomer, or prodrug at a time. Second, a comma is needed after “compound, solvent compound, and claim 3 to clearly separate it from the alternative forms.
Claims 17-19 recite “the compounds or pharmaceutically acceptable salts, esters, stereoisomers, solvent compounds or prodrugs thereof according to claim 3.” First, the plural language-compounds, salts, esters, stereoisomers, solvent compounds, or prodrugs-is unclear, as it suggests multiple forms simultaneously. The claims should be clarified to indicate whether it covers a single salt, ester, stereoisomer, or prodrug at a time. Second, a comma is needed after “compound and solvent compound to clearly separate it from the alternative forms.
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 1-3 and 5-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1 recites a compound of a formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, solvent compound or prodrug thereof
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The claim promises a broad genus of compound of the formula (I), a broad genus of pharmaceutically acceptable salt of the compound of the formula (I), a broad genus of prodrug of the compound of the formula (I), and a broad genus of ester of the compound of the formula (I). The only compound species described in the specification as filed are
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as the only representative species and no other pharmaceutically acceptable salt species of the compounds other than SP3103, and no other esters/prodrugs of species other than SP3102. Moreover, the specification does not describe any compound species of the formula (I) other than compounds SP3101, SP3103, and
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.The compounds of the formula (I) species that are described in the specification include compounds of the formula (I) wherein R1 = OH, -OC(O)-CH3, -OCH3;
R2 = H and -OC(O)-CH3;
R3 = -O(CO)-CH3;
R4 = H;
R5 = H and -C(O)-CH3; and
R6 = H.
This is a written description rejection.
The claims recite a broad genus of compound of the formula (I), a broad genus of pharmaceutically acceptable salt of the compound of the formula (I), a broad genus of prodrug of the compound of the formula (I), and a broad genus of ester of the compound of the formula (I).
M.P.E.P. #2163 states: “An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention….one must define a compound by ‘whatever characteristics sufficiently distinguish it’. A lack of adequate written description issue also arises if the knowledge and level of skill in the art would not permit one skilled in the art to immediately envisage the product claimed from the disclosed process”.
The claims encompass any compound of the formula (I), any pharmaceutically acceptable salt of the compound of the formula (I), any prodrug of the compound of the formula (I), and any ester of the compound of the formula (I). Accordingly, there is insufficient written description encompassing every compound of the formula (I), every pharmaceutically acceptable salt of the compound of the formula (I), every prodrug of the compound of the formula (I), and every ester of the compound of the formula (I), because the relevant identifying characteristics of the genus such as structure or other physical and/or chemical characteristics of the genus compound claimed and the genus pharmaceutically acceptable salt, the genus prodrug and the genus ester are not set forth in the specification as-filed, commensurate in scope with the claimed invention. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed” (see page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed” (see Vas-Cath at page 1116).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
M.P.E.P. 2163 II-A-3-a ii) states: “The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus (see i) (C), above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) (Claims directed to PTFE dental floss with a friction-enhancing coating were not supported by a disclosure of a microcrystalline wax coating where there was no evidence in the disclosure or anywhere else in the record showing applicant conveyed that any other coating was suitable for a PTFE dental floss.)”.
In the instant case, Applicant discloses a broad genus of compound of the formula (I), a broad genus of pharmaceutically acceptable salt of the compound of the formula (I), a broad genus of prodrug of the compound of the formula (I), and a broad genus of ester of the compound of the formula (I). Applicant does not have to list every possible substitution for the compound of the formula (I), pharmaceutically acceptable salt, prodrug and ester thereof that would be impractical fi the scope is broad. Instead, applicant need provide enough examples from different corners of the range to represent them fairly. This means applicant should give concrete examples that reflect the diversity of what they’re claiming. The claims recite a large set of passible R-groups and possible salts, prodrugs, and esters of the compounds and applicant needs to show at least a reasonable sampling of them-not necessarily every single one, but enough so that a skilled person can see applicant truly envisioned the whole range.
With respect to the compound of the formula (I), pharmaceutically acceptable salt of the compounds, prodrug, or ester thereof, the specification does not disclose sufficient guidance on how to make them. Even if the specification provides guidance on how to make them, the absence of least concrete examples of a compound of the formula (I), a salt form, a prodrug form, or an ester form of that disclosed species raises said written description concern.
Given the broad scope of the compounds claimed that can satisfy the claimed preambles, applicant has not provided sufficient written description (only one example in the specification) that would allow the skilled artisan to recognize that applicant was in possession of the genus of single disclosed oral tablet dosage form, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus. Thus, Applicant was not in possession of the claimed genus. See University of California v. Eli Lilly and Co. 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997).
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 1-3 and 16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention.
This rejection covers the embodiment of inflammation disorder.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The claimed compound of the formula (IV-g) is taught to have AHR agonistic activity in assays (in vitro). However, Applicant has not established a nexus between the in vitro and in vivo data and any other of the myriads of diseases or conditions (both prevention and treatment) recited encompassed by the claim.
The teachings in the art of record at the time of instant invention was made do not overcome the deficiencies in the instant disclosure.
With respect to inflammatory disease; Inflammation is the reaction of vascularized tissue to local injury; it is the name given to the stereotyped ways tissues respond to noxious stimuli. These occur in two fundamentally different types. Acute inflammation is the response to recent or continuing injury. The principal features are dilatation and leaking of vessels, and recruitment of circulating neutrophils. Chronic inflammation or "late-phase inflammation" is a response to prolonged problems, orchestrated by T-helper lymphocytes. It may feature recruitment and activation of T- and B-lymphocytes, macrophages, eosinophils, and/or fibroblasts. The hallmark of chronic inflammation is infiltration of tissue with mononuclear inflammatory cells. Mechanistically, chronic inflammation encompasses a broad spectrum of immunologic processes, including antibody formation, antibody-dependent cell-mediated cytotoxicity, and cell-mediated immunity (delayed-type hypersensitivity). Granulomas are seen in certain chronic inflammation situations. They are clusters of macrophages which have stuck tightly together, typically to wall something off. Granulomas can form with foreign bodies such as aspirated food, toxocara, silicone injections, and splinters.
Otitis media is an inflammation of the lining of the middle ear and is commonly caused by Streptococcus pneumoniae and Haemophilus influenzae. Its numerous forms include acute suppurative otitis media, chronic tubotympanic suppurative otitis media, chronic atticoantral suppurative otitis media, acute nonsuppurative otitis media, chronic serous otitis media, chronic mucoid otitis media, allergic seromucinous otitis media, exudative transudative otitis media, catarrhal serous otitis media, allergic otitis media and chronic purulent otitis media.
Myringitis (sometimes included with otitis externa) is inflammation of the tympanic membrane. It comes in numerous forms. Acute myringitis can occur because of direct trauma to the tympanic membrane through penetration by a foreign body. Primary myringitis may also be caused by unsuccessful removal of a foreign body, typically an insect, or by self-cleaning of the ear. Acute bullous myringitis and acute hemorrhagic myringitis can both be the consequence of a bacterial or viral infection. Fungal myringitis can be the consequence of a fungal infection. Eczematous myringitis can occur in cases of dermal eczema of the tympanic membrane's epidermis. Myringitis granulosa occurs when the tympanic membrane is covered with granulation tissue, and can result in destroying the tympanic membrane.
Idiopathic inflammatory medial meatal fibrotizing otitis is a disorder of the external auditory canal characterized by desquamation of the medial canal skin, chronic inflammation, and eventual canal stenosis.
Otitis externa (also known as "Swimmer's ear") is an inflammation of the outer ear and ear canal. The chronic form may be secondary to eczema, whereas the acute form tends to be in response to a microbial infection. Perichondritis of auricle, cholesteatoma of external ear and keratosis obturans are generally included with this.
Otitis interna (labyrinthitis) is an inflammation of the inner ear that typically results in severe vertigo and is generally thought to arise from a viral infection. from a viral inflammation. Treatment is generally with vestibular suppressants (suppression of symptoms), but antibiotics may be given in bacterial infection is suspected.
There is also Eustachian salpingitis, a general category of inflammation of the Eustachian tubes. It includes Otosalpingitis inflammation of the mucous membrane of the cartilagenous portion of the eustachian tube.
Petrositis is a type of inflammation of the temporal bone which may go all the way to the inner ear. Gradenigo's syndrome is a closely related disorder. Mastoiditis is an inflammation arising from infection of mastoid process, another portion of the temporal bone.
Cystitis is any inflammation of the bladder, often caused by bacteria. Two ordinary types are eosinophilic and tuberculous cystitis. Interstitial cystitis (IC) is a particularly severe form, an inflammation of the bladder wall which may include Glomerulations. The origins and mechanism are largely unknown, and it isn’t even clear whether there is just one form of the disease or several. There is no actual pharmaceutical treatment for the disease itself, although a few drugs can give some relief of symptoms, specifically Elmiron and DMSO.
Blepharitis is a chronic inflammation of the eyelids that is caused by a staphylococcus. Dacryocystitis is inflammation of the tear sac, and usually occurs after a long-term obstruction of the nasolacrimal duct and is caused by staphylococci or streptococci. Preseptal cellulitis is inflammation of the tissues around the eye, and Orbital cellulitis is an inflammatory process involving the layer of tissue that separates the eye itself from the eyelid. These life-threatening infections usually arise from staphylococcus. Hence, these types of inflammations are treated with antibiotics.
There is also a wide assortment of forms of conjunctivitis, including seasonal allergic conjunctivitis, perennial allergic conjunctivitis, giant papillary conjunctivitis (GPC) (a chronic yet poorly condition associated with contact lens wear), Vernal keratoconjunctivitis and atopic keratoconjunctivitis. In addition to types of allergic conjunctivitis there is also bacterial conjunctivitis (e.g. from Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus) and viral conjunctivitis (e.g. from gonorrhea, herpes simplex, chlamydia, adenoviruses or enteroviruses) Parasitic conjunctivitis (e.g. from Onchocerca volvulus, Loa loa, Wuchereria bancrofti or Trichinella spiralis), fungal conjunctivitis (e.g. from Candida albicans or Sporothrix schenckii), Phlyctenular Conjunctivitis, Inclusion Conjunctivitis, immunologic conjunctivitis, irritant conjunctivitis (e.g. from burns, chlorine or air pollutants ), Radiation conjunctivitis, and assorted forms of neonatal conjunctivitis (which can be caused by e.g. a blocked tear duct).
Cholecystitis is gallbladder inflammation usually caused by a gallstone that cannot pass through the cystic duct. In those cases, it normally cannot be treated by pharmaceuticals but instead the gallbladder is removed. Cholecystitis without the formation of gallstones, called acalculous cholecystitis, is caused by bacteria such as Salmonella, Staphylococcus, Streptococcus (as part of scarlet fever), and leptospirosis, and thus may be treatable by treating the underlying infectious agent. Acute inflammation of the gall bladder can also arise from typhoid; treatment is with antibiotics.
Arthritis is general term denoting group of conditions involving damage to the joints of the body, and may or may not involve inflammation of other parts of the body such as the nails.
Rheumatoid arthritis is an inflammatory disorder causing destruction of articular cartilage. It is an autoimmune condition where the body’s immune system attacks its joints. It is a multisystemic disease, having extra-articular manifestations (e.g. anemia, Keratoconjunctivitis sicca, lung fibrosis) which distinguish this disease from osteoarthritis.
Osteoarthritis is a degenerative disease, primarily of the articular cartilage and subchondral bone. Primary osteoarthritis, which comes in 2 forms, nodal and erosive, has no clearly defined underlying cause, although genetic factors are believed relevant in more than half the cases. Secondary osteoarthritis arises from injuries, diseases such as Paget's disease, conditions such as Marfan syndrome and long-term obesity, congenital disorders of joints, etc.
In gouty arthritis, joint inflammation is caused by the formation of monosodium urate monohydrate (MSU) crystals, or uric acid crystals, within the joint space.
Pseudogout, another form of arthritis, arises from the deposition of calcium pyrophosphate dihydrate (CPPD) crystals in synovial fluid or articular tissue.
In addition, CPPD deposition can cause Pseudo-osteoarthritis, a gradual onset of joint pain and stiffness, which commonly involves an unusually severe, oddly distributed, degenerative arthritis.
CPPD deposition can also cause Pseudo-rheumatoid arthritis, which features multiple joint involvement with symmetric distribution, morning stiffness, fatigue, and synovial thickening.
Finally, CPPD can cause Pseudo-neuropathic anthropathy, a severe destructive monarthritis similar to that seen in neuropathic joints.
Hydroxyapatite (also called Basic calcium phosphate (BCP)) induced arthritis, from Hydroxyapatite deposition disease (HADD), is a third category of crystal deposition disease. This can involve synovial effusions, acute inflammation in joints, idiopathic tumoral calcinosis, Milwaukee shoulder syndrome etc. There is also an erosive arthritis associated with BCP crystals.
A fourth form is calcium oxalate associated arthritis, typically arising from end stage renal disease, but also from short bowel syndrome; diets rich in rhubarb, spinach or ascorbic acid; thiamine or pyridoxine deficiency; and a metabolic problem, primary or secondary oxalosis.
Finally, there are assortments of other crystal-associated forms of arthritis. Calcium oxalate aluminum phosphate crystals can trigger an acute arthritis in patients on renal dialysis. Cholesterol, xanthine, cystine, cryoglobulins, Charcot-Leyden (lysophospho-lipase), and hypoxanthine crystals when depositing in joints produce their own forms of arthritis.
Lyme disease (Lyme borreliosis), which is caused by spirochetal bacteria from the genus Borrelia, triggers several forms of arthritis, including types of radiculoneuritis such as neuroretinitis, myelitis and encephalomyelitis, as well as Lyme arthritis and cerebral arteritis.
There is an assortment of other forms of infectious arthritis, i.e. arthritis caused by bacteria, rickettsiae, mycoplasmas, viruses (or vaccinations given to prevent viral infections), fungi, or parasites; it is also called septic arthritis. Included in this category are various types of mycotic arthritis, and viral arthritis, such as rubella arthritis, Mumps arthritis, arboviral arthritis, syphilitic arthritis, parvovirus arthritis, tuberculous arthritis, Varicella arthritis, gonococcal arthritis, rubella arthritis, etc. These assorted disorders can arise from quite varied sources. Moreover, there is also a poorly understood disorder, pseudoseptic arthritis. Reactive arthritis (also been known as Reiter's Syndrome, arthritis urethritica, and polyarteritis enterica) is an autoimmune condition that develops in response to an infection in another part of the body, although reactive arthritis often shows up after the triggering infection is either gone or in remission. The most common triggers are Chlamydial infections, Nisseria gonorrhea; Salmonella, Shigella, and Campylobacter. Another of the seronegative spondyloarthropathies is psoriatic arthritis, which is believed to be autoimmune in origin and whose exact cause is unknown, but there is a clear genetic component. It comes in several forms, including symmetric, asymmetric, arthritis mutilans, and “distal interphalangeal predominant”. Enteropathic arthritis, also a seronegative spondyloarthropathy is secondary to IBD.Other seronegative spondyloarthropathies are ankylosing spondylitis (also known as Bechterew syndrome; Marie Strumpell disease; and rheumatoid spondylitis), and undifferentiated seronegative arthritis. All of the seronegative spondyloarthropathies are distinct from rheumatoid arithitis, in that in RA, the Rf-factor is not absent. Sjogren's syndrome, like RA an autoimmuine, Seropositive disorder, affects primarily the eyes and mouth, but extraglandular problems in Sjogren's syndrome include joint pain or inflammation. It is not entirely clear whether Sjogren's syndrome arthritis is actually different from RA.
Ochronotic arthritis is a degenerative form of arthritis, causing a color change in the joints, and hardening of tendons and ligaments can predispose them to rupture; microruptures cause further joint disease. Lupus arthritis is the most common manifestation of Systemic Lupus Erythematosus (SLE), an auto-immune condition. The most commonly affected joints are the hands, wrists, and knees.There is also Adult Still's disease (ASD or AOSD) which has in addition to joint inflammation, a salmon-pink rash and daily spiking fevers. Related is Systemic onset juvenile idiopathic arthritis (SOJIA, also known as Still's disease). Menopausal arthritis is due to ovarian hormonal deficiency, typically arising from use of aromatase (estrogen synthetase) inhibitors, which lower levels of estrogen. This has been little studied.
Neuropathic arthritis (which comes in several forms, the most important of which is Charcot's joint disease or Charcot Arthropathy or Charcot's arthritis) can arise from sources as diverse as Diabetes Mellitus, steroid treatment, leprosy, chronic alcoholism, heavy metal poisoning and neoplastic peripheral neuropathy. Hallux rigidus, of unknown etiology, is a degenerative type of arthritis that affects the large joint at the base of the big toe. Arthritis secondary to Systemic Sclerosis (other than RA) is usually symmetrical polyarthritis with predominant hand involvement, and is frequently erosive.
Hemorrhagic Arthritis (including haemophilic arthritis) is a general term encompassing any disorder characterized by bleeding within a joint, leading to inflammation of the joint lining (e.g. chronic synovitis), and sometimes degeneration of joint cartilage. Depending on cause, it is either acute or chronic. The great majority of those suffering from severe hemophilia have haemophilic arthritis.The Palmar Fasciitis and Polyarthritis Syndrome is a disabling, paraneoplastic condition of unknown pathogenesis. Complicating matters further is that fibromyalgia is considered by some to be included in the term arthritis, but others do not consider it a form of arthritis.Sinusitis is the inflammation of the mucosal lining of one or more of the 4 cavities near the nasal passages (ethmoid, maxillary, frontal, and sphenoid sinuses). It commonly accompanies upper respiratory viral infections which obstruct the opening, but such obstruction can also arise from abnormalities in the structure of the nose, enlarged adenoids, diving/swimming, infections from a tooth, and trauma to the nose, and foreign objects that are stuck in the nose. Bacteria, notably Streptococcus pneumonia, Haemophilus influenza, and Moraxella catarrhalis grown in the trapped secretions. In most cases it requires no treatment, but antibiotics may be given, along with acetaminophen for pain and nosedrops, for relief of symptoms. Pharyngitis is infection and inflammation of the throat (including the nasopharynx, uvula, and soft palate) and tonsillitis is of the tonsils. These are caused by a variety of viruses (adenoviruses, influenza viruses, parainfluenza viruses, Epstein-Barr virus, enteroviruses, Herpes simplex virus), mycoplasmas (e.g. Mycoplasma pneumoniae), and bacteria (Group A Beta Hemolytic Streptococci (GABHS), Streptococcus pyogenes, Neisseria Gonorrhea, Hemophilus Influenza Type B) as well as fungal infections, parasitic infections, cigarette smoke, and unknown causes.
Similarly, Osteomyelitis is the inflammation of bones, often caused by bacteria (most commonly Staphylococcus Aureus), and sometimes by fungi or viruses. Chronic Recurrent Multifocal Osteomyelitis (CRMO), a chronic inflammatory disease of unknown etiology, results in recurrent fever and the development of multiple inflammatory bone lesions.
Dacryoadenitis, an inflammation of the tear gland, can arise from infectious mononucleosis, mumps, gonorrhea, or influenza.
Lung inflammation can take many forms.
Chronic Obstructive Pulmonary Disease (COPD) is a slowly progressive disease of the airways that is characterized by a gradual loss of lung function. COPD includes chronic obstructive Bronchitis (which involves inflammation and eventual scarring of the bronchi) and emphysema (enlargement and destruction of the alveoli). Emphysema comes in several forms, including Congenital Lobar Emphysema, Bullous Emphysema, Centrilobular Emphysema (Proximal acinar emphysema), Panacinar (panlobular), Distal acinar (paraseptal) as well as Alpha-1 antitrypsin (AAT) deficiency, which is the genetic form of emphysema; patients often have both a form of bronchitis and emphysema. Ordinary chronic bronchitis is sometimes included with COPD even if there is no actual obstruction, and asthmatic bronchitis is generally included in COPD as well. Persons with COPD typically develop smaller air passageways, which can become clogged with mucus and have partially destroyed alveoli. There is no pharmaceutical treatment for COPD per se. Instead, treatment is supportive and designed to relieve symptoms and improve quality of life. Thus, oxygen is often given to partially compensate for the loss of lung function. Bronchodilators can expand passageways in the lungs, Corticosteroids can reduce inflammation and Antibiotics can ward off bacterial infections, but none of these treat the COPD itself.
Another category of inflammatory disorders of the lung is Interstitial lung disease, or ILD, (interstitial pulmonary fibrosis), a term that includes more than 180 chronic lung disorders, which may be chronic, nonmalignant (non-cancerous) and noninfectious. Interstitial lung diseases are named after the tissue between the air sacs of the lungs called the interstitium -- the tissue affected by fibrosis (scarring). The common link between the many forms of ILD is that they all begin with an inflammation. The three main kinds are bronchiolitis - inflammation that involves the bronchioles (small airways); alveolitis - inflammation that involves the alveoli (air sacs); and vasculitis - inflammation that involves the small blood vessels (capillaries). More than 80 percent of interstitial lung diseases are diagnosed as pneumoconiosis, a drug-induced disease, or hypersensitivity pneumonitis. An important group of the ILDs are the Idiopathic interstitial pneumonias including idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, acute interstitial pneumonia, Respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia and lymphoid interstitial pneumonia. Other ILDs are bronchiolitis obliterans, histiocytosis X, chronic eosinophilic pneumonia, granulomatous vasculitis, Goodpasture’s syndrome and pulmonary alveolar proteinosis. The cause of interstitial lung disease is not known; however, a major contributing factor is thought to be inhaling environmental pollutants. Other contributing factors include Sarcoidosis, certain drugs, radiation, connective tissue or collagen diseases and family history. Treatments may include corticosteroids, influenza or pneumococcal pneumonia vaccine but these are of limited effectiveness.
Lung inflammation includes most Occupational Lung Diseases, arising from repeated and long-term exposure to certain irritants on the job. These include for example asbestosis, coal worker’s pneumoconiosis (caused by inhaling coal dust), silicosis (caused by inhaling free crystalline silica), byssinosis (caused by dust from hemp, flax, and cotton processing, also known as brown lung disease), aluminosis, anthracosis (“collier's lung”, from the accumulation of carbon from inhaled smoke or coal dust in the lungs), chalicosis (stone-cutters' lung disease, due to inhaling stone dust), siderosis (occurring in iron workers, produced by the inhalation of particles of iron), tabacosis. Some of these are grouped together as hypersensitivity pneumonitis. These include Farmer's Lung arising from fungus spores from e.g. Moldy hay, Bird-Breeder's Lung, arising from various bird proteins, Humidifier Lung, arising from bacterias fungi, and even amoebae found in mists, from standing water, Malt Worker's Lung from moldy barley, and many other forms. There is also Radiation pneumonitis, a consequence of radiation therapy done to the chest, generally for lung or breast cancer. Lung inflammation includes Pneumonia. Lobar pneumonia affects one or more sections (lobes) of the lungs. Bacterial pneumonia is caused by various bacteria notably Streptococcus pneumoniae. Viral pneumonia is caused by viruses (such as respiratory syncytial, parainfluenza, and influenza). There is no clearly effective treatment for viral pneumonia. Pneumonia can also occur as a hypersensitivity, or allergic response, or from mycoplasmas, rickettsias (especially Q fever), and Chlamydia. Eosinophilic pneumonia, also called eosinophilic pneumonitis includes Löffler's syndrome and similar pneumonias such as tropical eosinophilia. These do not have alveoli infected by bacteria, viruses, or fungi, but instead, the alveoli and often the airways do fill with eosinophils. Why the eosinophils accumulate in the lungs is not well understood, and it can be triggered by things as varied as penicillin, fungi and parasites. Chronic eosinophilic pneumonia (CEP, also called Carrington's eosinophilic pneumonitis) is a related but somewhat different syndrome, and can easily be life threatening.
Asthma is a family of disorders the most important of which are extrinsic asthma (an allergic disorder mediated by IgE, generally considered an immune disorder), and intrinsic asthma (non-allergic, generally a response to irritants such as smog or cigarette smoke, but also can arise from some infections, such as forms of sinusitis, or from gastrointestinal reflux). Intrinsic asthma is associated with nasal polyps and massive eosinopillic infiltration of the respiratory mucous membrane, but serum levels of immunoglobulin E are within the normal range. There is also mixed asthma (both of the above), occupational asthma (a response to workplace chemicals such as toluene or certain metals), exercise induced asthma, and cough variant asthma. Asthma is characterized by bronchial wall hyperresponsiveness, viz., bronchoconstriction followed by bronchial inflammation.
Chronic bronchitis is a long-term inflammation of the bronchi, which results in increased production of mucus, as well as other changes. Chronic bronchitis has no specific organism recognized as the cause of the disease. Cigarette smoking is cited as the most common contributor to chronic bronchitis, followed by bacterial or viral infections and environmental pollution. Treatment is purely supportive and may include bronchodilators for inhaled medications, oxygen supplementation, and lung reduction surgery and lung transplantation.
Acute bronchitis is the inflammation of mucous membranes of the bronchial tubes and is usually caused by infectious agents such as bacteria or viruses. It may also be caused by physical or chemical agents -- dusts, allergens, strong fumes -- and those from chemical cleaning compounds, or tobacco smoke. (Acute asthmatic bronchitis may happen as the result of an asthma attack, or it may be the cause of an asthma attack.) Acute bronchitis is usually a mild, and self-limiting condition, with complete healing and return to function. Most of the treatment is supportive of the symptoms, and may include analgesics, such as acetaminophen for fever and discomfort.
Another disease characterized by lung inflammation is Cystic fibrosis (CF), characterized by an abnormality in the glands that produce sweat and mucus. It is chronic, progressive, and is usually fatal. The basis for the problem with CF lies in an abnormal gene, which results in an atypical electrolyte transport system within the cells of the body. The abnormal transport system causes the cells in the respiratory system, especially the lungs, to absorb too much sodium and water. This causes the normal thin secretions in the lungs to become very thick and hard to remove. The high risk of infection in the respiratory system leads to damage in the lungs, and eventually death of the cells in the lungs. The etiology of chronic inflammation, however, remains unclear. The disorder itself is largely untreatable.
Acute (or Adult) respiratory distress syndrome (ARDS) is severe inflammation in both lungs resulting in an inability of the lungs to function properly, arising from damage to capillary endothelium and alveolar epithelium caused by leukotrienes, oxidants, platelet-activating factor, and/or proteases. ARDS is a devastating, often fatal, inflammatory lung condition that, unlike most lung disorders, usually occurs in conjunction with catastrophic systemic conditions, especially shock, sepsis, and non-pulmonary trauma. No specific pharmaceutical therapies currently exist for ARDS per se. Treatment primarily involves supportive care in an intensive care unit, including use of a mechanical ventilator and supplemental oxygen to help patients breathe, plus in some cases, treatment of the underlying disorder (typically, sepsis) which has triggered the ARDS. Acute Lung Injury is the same clinical disorder, differing only in having a lesser degree of hypoxemia.
Myocarditis is an inflammation of the muscular middle layer of the heart (myocardium) Viruses, bacteria, and noninfectious diseases can cause it. Treatment is primarily supportive e.g. drugs may be used to improve the heart's ability to contract and to remove extra fluids from the body. Unless the underlying infectious agent itself is treatable, this inflammation is not itself treated.
Mucocutaneous lymph node syndrome (MLNS) or Kawasaki syndrome is a potentially fatal inflammatory disease that affects the heart, circulatory system, mucous membranes, skin, and immune system. Its cause is unknown.
Glossitis is inflammation of the tongue. Local causes of glossitis include bacterial or viral infection, mechanical irritation or injury from burns, rough edges of teeth or dental and oral appliances, or other trauma; exposure to irritants (tobacco, alcohol, hot foods, or spices), and sensitization (to e.g. toothpaste, mouthwash, breath fresheners, dyes in candy, plastic in dentures or retainers) anemia and other B vitamin deficiencies, erythema multiform, pemphigus vulgaris, syphilis, and other disorders. It can be inherited. Corticosteroids such as prednisone may be given to reduce the inflammation. Antibiotics, antifungal medications, or other antimicrobials may be prescribed if the cause of glossitis is an infection. Anemia and nutritional deficiencies must be treated, often by dietary changes or other supplements.
Meningitis is the inflammation of the meninges—the surrounding 3-layered membranes of the brain and spinal cord, and the fluid it is bathed in, (CSF). It can be caused by virtually any known infectious agent. Thus, if it is caused by Haemophilus influenzae or Neisseria meningitis, the antibiotic derivative rifampin would be used.
Inflammatory aortic aneurysms can be in the ascending or more commonly descending areas, and these disorders are poorly understood, but in some cases involve the presentation of an unknown antigen on the aortic wall.
Myelitis is any inflammation of the spinal cord. Dactylitis is an inflammatory affection of the fingers. There is an entire family of Idiopathic Inflammatory Myopathies, generally named as forms of myositis. Polymyositis produces pain, with marked weakness and/or loss of muscle mass in the proximal musculature, particularly in the shoulder and pelvic girdle, and can also include sclerodactyly, dysphagia and other aspects of esophageal dysmotility, low grade fever and peripheral adenopathy.
Dermatomyositis, considered a type of autoimmune connective tissue disease, produces skin rash and symmetric proximal muscle weakness which can be as severe as complete paralysis. There is a variant form, juvenile dermatomyositis, with the same general symptoms but also including Calcinosis cutis.
Sporadic inclusion body myositis (s-IBM) and hereditary inclusion body myopathies (h-IBM) encompass a group of disorders sharing the common pathological finding of vacuoles and filamentous inclusions. These constitute an inflammatory slowly progressive proximal myopathy which may cause dysphagia and mild to moderate muscle wasting. Its pathogenesis is unknown, but ubiquitin, prion protein, and tau protein has been found in these inclusions. S-IBM has some evidence of being an autoimmune disorder and some evidence of being a primarily degenerative disorder, But neither theory fits well the complex series of changes seen in this disorder. The endomysial infiltrates in patients with s-IBM are composed of CD8+ T cells, macrophages in a 2:1 ratio, myeloid dendritic (antigen-presenting) and CD138+ plasma cells. Myofibers in s-IBM exhibit vacuolization, atrophy, abnormal myonuclei, and deposits of amyloid-β (Aβ), phosphorylated tau (p-tau), apolipoprotein E, presenilin-1, the normal cellular isoform of prion protein (PrPc), and many other characteristic proteins, leading to suspicion of prion involvement.
Hereditary Inclusion Body myositis (HIBM1) is based on the Desmin gene and is a dominant genetic disorder.
Hereditary inclusion body myositis type 2 (HIBM2) is an autosomal recessive adult-onset myopathy due to mutations in the GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) gene. It appears to be the same disorder as Nonaka distal myopathy.
A third form, hereditary inclusion body myopathy with Joint Contractures & Ophthalmoplegia (IBM3), is a Myosin heavy chain IIa disorder.There are forms of Eosinophilic myositis, including eosinophilic fasciitis, eosinophilic mono/multiplex myositis, esinophilic polymyositis and eosinophilia – myalgia syndrome. Usually included in this category is Myositis ossificans, including Myositis ossificans circumscripta and progressive myositis ossificans.
Focal myositis seems to be a macrophage and T-cell–rich lesion that changes to B cell and dendritic plasmacytoid cells, and is classified as an inflammatory pseudotumor of skeletal muscle.
There is also a Giant-cell myositis, generally seen in association with giant-cell myocarditis, myasthenia gravis, auto-immune thyroiditis, and thymoma.
There are also the general categories of myositis associated with collagen vascular disease and myositis associated with malignancy.
Behçet's disease is a syndrome of unknown origin, but appears to be an autoimmune disorder. It is characterized primarily by inflammation of the blood vessels. Symptoms include a broad range of problems, which include mouth sores, genital sores, skin sores or lesions, meningoencephalitis, Uveitis, inflammation of the joints, thrombophlebitis, aneurysms, digestive tract ulceration (sometimes called Behçet's colitis)
Encephalitis is inflammation of the brain itself, often caused by a group of arboviruses. Treatment of encephalitis is largely supportive because no specific antiviral agents, except for that which works against herpes simplex virus, are available for therapy.
Inflammation in the brain is a significant component of some important neurodegenerative conditions, including Alzheimer's Disease, AIDS dementia, Pick’s Disease, Parkinson’s Disease, and Huntington’s Disease. The circumstances here are poorly understood because while there does not appear to be lympho-infiltrative processes, there is neuropathological evidence for immune activation. Thus, inflammation may be a disease-aggravating or even a disease-ameliorating factor in pathogenesis, or a non-contributory consequence of the injurious cascade of neurodegeneration and thus incidental.
Hepatitis is an inflammation of the liver, usually caused by viral invasion, notably hepatitis A, B and C, but sometimes Epstein-Barr virus; herpes simplex viruses; measles, mumps, and chicken pox viruses; and cytomegaloviruses. Treatment, when possible, is with antivirals. Inflammation of the liver also takes the form of alcoholic hepatitis. Lupoid hepatitis is an autoimmune disorder. Idiopathic inflammatory trigeminal sensory neuropathy (IITSN) affects the head, producing face numbness, headache, and hemifacial pain attacks.
Hemorrhoids are an enlarged or varicose condition of the hemorrhoidal veins and tissues around the anus, either internal or external. Anything which obstructs the free circulation of the blood in the portal system will give rise to hemorrhoids. Constipation, straining at stool, diarrhea, dysentery, rough toilet paper, uncleanliness, pelvic tumors, displacement of the uterus and pregnancy are among the most common causes.
Rosacea classically presents with patchy flushing and redness and inflammation, particularly on the cheeks, nose, forehead, and around the mouth. Rosacea is persistent and commonly worsens with time, sometimes with the formation of pustules and swelling. Triggers for rosacea are extremely varied and include things not ordinarily associated with inflammation, such as drinking alcohol and hot beverages, or even ordinary social interactions.
There is a series of inflammatory problems directly connected to neutrophil-endothelial cell adhesion (NECA). These include frostbite injury, bacterial meningitis, acute airway inflammation, allograft rejection, hemorrhagic shock, septic shock, ischemia and reperfusion injuries.
Immune reconstitution inflammatory syndrome (IRIS), also known as immune restoration disease and immune restoration inflammatory syndrome is a peculiar syndrome that occurs after a desirable gain in immunocompetence, usually arising from successful treatment of HIV-infected subjects. Although numerous infectious and noninfectious causes have been proposed, its pathogenesis remains unclear. IRIS can present in a variety of ways especially if there is an underlying infection, such as with leprosy or tuberculosis CMV to which the body is suddenly able to (over) react to, but in other cases, the diseases appear to be non-infective, such as with SLE or RA.
Urethritis is an inflammation of the duct that leads from the bladder to the body's exterior. It is often due to fecal contamination or irritation due to physical or chemical substances (e.g. introduction of foreign bodies into the urethra, bubble bath, or soap) or gonorrhea. Treatment may simply involve the withdrawal of the offending chemical agent, or the administration of antibiotics, when Neisseria gonorrhoeae is involved.
Inflammation can arise from the eruption of teeth in a child (teething).
Inflammation of the nails can arise from chronic paronychia, fungus (especially Candida albicans), trauma, impaired circulation, and dermatitis.
Bright's disease (or glomerulonephritis) is inflammation of the glomeruli and the nephrons, the structures in the kidney that produce urine. It usually results from an infection, such as a streptococcal infection, that occurs somewhere else in the body. There is no real treatment beyond relief of the symptoms.
Whipple's disease is a chronic, multisystem, relapsing inflammatory disease that usually affects the small intestine and mesenteric lymph nodes. Its cause is Whipple's bacillus.
Panniculitis is a group of diseases characterized by inflammation of subcutaneous adipose tissue. It occurs in four forms: lobular panniculitis without vasculitis (acute panniculitis, or Weber-Christian disease or systemic nodular panniculitis), lobular panniculitis with vasculitis, and septal panniculitis with or without vasculitis.
Thyroiditis is an inflammation of the thyroid gland, and takes three forms. Hashimoto's Thyroiditis (chronic lymphocytic thyroiditis) is the most common type of thyroiditis. It is an autoimmune disorder, and treatment is to start thyroid hormone replacement. For De Quervain's Thyroiditis (subacute or granulomatous thyroiditis), treatment is usually bed rest and aspirin to reduce inflammation. Occasionally cortisone and thyroid hormone may be used. Silent Thyroiditis usually arises following pregnancy. Treatment is usually bed rest with beta blockers.
Regional enteritis (Crohn's disease or ileitis) is an autoimmune disorder which is associated with the presence of Mycobacterium paratuberculosis. It can affect any part of the gastrointestinal tract but most commonly affects the ileum. The inflammation is controlled primarily by regulation of diet, antibiotics if abscesses and fistulas are present, sometimes Prednisone and other corticosteroids, and surgery.
Proctitis is a form of inflammation of the rectum, and includes Antibiotic-Induced Proctitis, Gonorrheal Proctitis, Herpetic Proctitis, Ischemic Proctitis, Radiation Proctitis, Syphilitic Proctitis and idiopathic proctitis.
Sarcoidosis is a multisystem disorder characterized by a cell-mediated Th1 immune response with formation of noncaseating granulomas. These granulomas generally heal and disappear on their own. However, for those granulomas that do not heal, the tissue can remain inflamed and become scarred, or fibrotic. Pulmonary sarcoidosis can develop into pulmonary fibrosis. Bronchiectasis, a lung disease in which pockets form in the air tubes of the lung and become sites for infection, can also occur. Treatment may include the use of corticosteroids.
Stomatitis, inflammation of the mouth, and mucositis, inflammation of the mucosa can arise from sources as diverse as Candida albicans, dentures, chemotherapy and radiation therapy to the head, neck or mouth ("Radiation mucositis"). It may be secondary to infection, trauma, systemic diseases or autoimmune mechanisms. These come in many forms, such as aphthous ulcers, and Acute Necrotizing Ulcerative Gingivitis i.e. "trench mouth". Herpetiform ulcers treatment has ranged from antibiotics, immunosuppressants and yogurt, to Lactobacillus capsules, tetracycline and systemic steroids. Palliative measures include topical anesthetics, Vitamin E, analgesics, and coating agents. Antiviral agents may be used if viral origin is established.
Allergic rhinitis, a reaction that occurs in the eyes, nose and throat, which exists in two forms, seasonal and perennial, is a Type I Antibody-Antigen reaction to allergens. T Lymphocytes and B Lymphocytes release IgE antibody; mast cells appear in skin and mucosa and degranulate, which is followed by release of histamine and chemotactic factors, prostaglandins and leukotrienes, and a response of intravascular basophils. Histamine causes inflammation and fluid production in the fragile linings of nasal passages, sinuses, and eyelids. The underlying disorder is not itself treated, except possibly via immunotherapy, in which there is administered gradually increasing doses of the allergen. Instead, symptoms are treated with drugs used to block the action of allergic mediators, or to prevent degranulation processes, such as anti-leukotrienes or antihistamines.
Nonallergic Rhinitis (including eosinophilic, rhinitis medicamentosa, vasomotor Rhinitis, neutrophilic rhinosinusitis, and others) also affects the eyes, nose and throat, and comes from fumes, odors, temperature or atmospheric changes, smoke, etc. Treatments for nonallergic rhinitis include oral medications, inhaled medications, immunotherapy, and surgery for some conditions.
Wegener's Granulomatosis is a disease that usually begins as a localized granulomatous inflammation of upper or lower respiratory tract mucosa and may progress into generalized necrotizing granulomatous vasculitis and glomerulonephritis. The cause is unknown. Although the disease resembles an infectious process, no causative agent has been isolated. Treatment is with immunosuppressive cytotoxic drugs.
Pancreatitis is inflammation of the pancreas and can arise from abdominal trauma, or the formation of gallstones that obstruct the common bile duct. It can be associated with excessive ingestion of alcohol; with disorders such as cystic fibrosis or Reye's syndrome; or with scorpion stings. Infectious causes include mycoplasmas, Epstein-Barr viruses, Coxsackie viruses, leptospirosis, hepatitis viruses, mumps, congenital German measles, Ascaris worms, and syphilis. The inflammation per se is generally not treatable. Treatment is usually supportive and consists of the management of pain and intravenous feeding.
Neuroretinitis is a type of inflammation of the retina. It is often idiopathic. It frequently arises secondary to some kind of infection, such as Hepatitis B, HSV, EBV, influenza A, mumps, Coxsackie B, TB, salmonella, Lyme disease, syphilis, leptospirosis, Histoplasmosis, Toxoplasmosis, toxocara, Sarcoidosis and cat-scratch disease. Treatment is thus to the underlying cause. For example, Diffuse unilateral subacute neuroretinitis (DUSN) arises from nematodes deep in the retina or in the subretinal space. Anthelminthic treatment is then used. When the origin is Toxoplasmosis, then anti-Toxoplasma medications such as Pyrimethamine. Vogt-Koyanagi-Harada syndrome (Harada's disease) is an acute inflammatory, immune-mediated disorder that can cause choroidal neovascularization, severe chorioretinal atrophy, and secondary glaucoma.
River blindness arises from inflammation of the eye caused by larvae (microfilaria) of the nematode Onchocerca volvulus, although the Wolbachia bacteria may be involved as well.
Multifocal choroiditis and panuveitis (MCP) is a posterior chorioretinal inflammatory disease of unknown etiology
There are also other forms of choroiditis, inflammation of the middle coat (choroid) of the eyeball, as well as uveitis, which is inflammation of the parts of the eyes that make up the iris. Other eye inflammations include scleritis and episcleritis, inflammation of tissues on the sclera. Pouchitis is an inflammation of an internal pouch (either the ileoanal pouch or the Koch pouch) created in patients who have part of their colon removed to treat ulcerative colitis or familial adenomatous polyposis (FAP).
Gastritis is inflammation to the stomach lining. Atrophic gastritis is characterized by the loss of the stomach cells that are responsible for manufacturing acid, pepsin, and intrinsic factor. This condition occurs in older people or those suffering from Helicobacter pylori. Erosive (hemorrhagic) gastritis occurs when shallow ulcers or sores develop on the upper layer of the stomach lining, usually because of the excessive ingestion of a stomach irritant such as aspirin or alcohol.
There can also be mentioned appendicitis, which can occur when a hard piece of stool blocks the opening of the appendix, causing swelling and inflammation.
There is an entire family of Idiopathic inflammatory-demyelinating diseases (IIDDs). The most common of these are the various forms of multiple sclerosis. These include relapsing-remitting MS, and secondary progressive multiple sclerosis, as well as
primary progressive MS and progressive relapsing MS as well as the so-called “benign MS” and the Marburg variant of MS. Baló’s concentric sclerosis is generally considered to be a variant of MS.
Acute disseminated encephalomyelitis is usually triggered by viral or bacterial infections or vaccinations and can be quite severe, and can be monophasic or relapsing. Acute hemorrhagic leukoencephalitis (Hurst encephalitis) is now thought to be a hyperacute form of ADEM. Bickerstaff encephalitis is usually included with ADEM as well.
Another IIDD is optic neuritis, either papillitis or retrobulbar neuritis, can occur be monophasic or in recurrent form, the latter of which is more likely to progress to MS. Brainstem inflammatory-demyelinating syndrome.
Acute transverse myelitis resulting in motor, sensory, and autonomic dysfunction can be idiopathic or develop in the context of viral, bacterial, fungal or parasitic infections, as well as in the course of systemic autoimmune diseases, and can be monphaisc or receuurent.
Other IIDDs include Devic’s neuromyelitis optica, and Schilder’s disease.
There are both Tumefactive or pseudotumoral IIDDs.
The great majority of skin problems involve some type of inflammation, such as response to physical injury (e.g. sunburn, ticks, abrasion, or a bee string), acute allergic contact dermatitis (such as poison ivy), and infections (such as boils and cold sores). Ingrown hairs, or pili incarnati, can cause acute pustular reactions. Cancerous lesions of the skin frequently show some degree of inflammatory response. Acne's inflammation is caused by leakage of sebum and keratin debris outside the distended pilosebaceous duct. The bacillus Propionibacterium acnes, which populate the lesions, may also contribute indirectly to this inflammation by metabolizing the sebum to produce irritant fatty acids. Inflammation in skin problems is usually the result of the release of chemical mediators in the skin, notably histamine, peptides (kinins) and fatty acids (prostaglandins and leukotrienes), which are formed enzymatically in response to e.g. injury. Medications designed to counteract inflammation in the skin may or may not antagonize the effects of the particular type of mediator involved, if that is known. The inflammation can take many different forms, including redness, (from dilation of blood vessels); heat, (from increased blood flow); swelling (from leakage of fluid from the small blood vessels); whealing reactions (hives, nettle rash, urticaria) in which vascular changes predominate, and pain or itching. Blisters (from enzymes released from inflammatory cells, resident cells of the skin, or blood plasma components) can cause the breakdown of proteins responsible for the structural integrity of the skin, leading to serious inflammatory disorders such as pemphigus. In addition, the affected skin may feel indurated (hardened) because of the deposition of the coagulation protein fibrin and the infiltration by inflammatory blood cells (lymphocytes, histiocytes, and polymorphonuclear leukocytes).
Prostatitis, inflammation of the prostate, comes in several different forms, including those of bacterial origins, and those which are not, including chronic abacterial prostatitis and asymptomatic inflammatory prostatitis. Certain types of anti-inflammatory agents, such as non-steroidal anti-inflammatory medications (Ibuprofen and naproxen) along with muscle relaxants can be used in the non-bacterial cases.
There are a number of different forms of vasculitis, including Churg-Strauss vasculitis, consecutive vasculitis, granulomatous vasculitis of central nervous system, hypersensitivity vasculitis, (called also allergic or leukocytoclastic vasculitis or leukocytoclastic angiitis which arises from hypersensitivity to an antigenic stimulus), hypocomplementemic vasculitis, isolated vasculitis of central nervous system, nodular vasculitis, overlap vasculitis (polyangiitis overlap syndrome), pulmonary vasculitis including Wegener's granulomatosis, rheumatoid vasculitis, segmented hyalinizing vasculitis (livedo vasculitis), Polyarteritis nodosa, and urticarial vasculitis. There are also specific forms of arteritis, including coronary arteritis, equine viral arteritis, giant cell arteritis (cranial, granulomatous, or temporal arteritis or Horton's disease), infantile arteritis, infectious arteritis, arteritis obli¢terans (endarteritis obliterans), rheumatic arteritis, syphilitic arteritis, Takayasu's arteritis (aortic arch, or brachiocephalic arteritis or Martorell's syndrome or pulseless disease; it is of unknown origin), tuberculous arteritis, endarteritis obliterans, and verminous mesenteric arteritis.
Angular cheilitis (also called perlèche, cheilosis or angular stomatitis) is an inflammatory lesion at the corner of the mouth. These generally arise from nutritional deficiencies, either from poor diet or malabsorption syndromes, and can because infected with fungus as well.
Seborrhoeic dermatitis, which includes seborrhoea capitis (Cradle cap), seborrhoeic infantile dermatitis and other seborrhoeic forms is a chronic disease characterized by scaling on an erythematous base. Pityriasis simplex capillitii (dandruff) is often included with this category.
Pustular dermatitis is an inflammation of the skin that presents with pustular lesions, and includes eosinophilic pustular folliculitis (Ofuji's disease), Reactive arthritis (Reiter's syndrome), and Subcorneal pustular dermatosis (Sneddon–Wilkinson disease).
Psoriasis is a chronic, and recurrent inflammatory disease of the skin characterized by circumscribed, erythematous, dry, scaling plaques. The psoriasis family includes annular pustular psoriasis, drug-induced psoriasis, generalized pustular psoriasis, guttate psoriasis, inverse psoriasis, keratoderma blennorrhagica (keratoderma blennorrhagicum), localized pustular psoriasis, napkin psoriasis, psoriasis, vulgaris, psoriatic arthritis, psoriatic erythroderma (erythrodermic psoriasis), seborrheic-like psoriasis (sebopsoriasis, seborrhiasis).
Lichenoid eruptions are dermatoses associated with the inflammatory disorder lichen planus and can arise from varied sources. These include annular lichen planus, atrophic lichen planus, bullous lichen planus (vesiculobullous lichen planus), erythema dyschromicum perstans (ashy dermatosis, dermatosis cinecienta), hepatitis-associated lichen planus, hypertrophic lichen planus (lichen planus verrucosus), idiopathic eruptive macular pigmentation, keratosis lichenoides chronica (Nékam's disease), kraurosis vulvae, lichen nitidus, lichen planus actinicus (actinic lichen planus), lichen planus pemphigoides, lichen planus pigmentosus, lichen planus–lichen sclerosus overlap syndrome, lichen planus–lupus erythematosus overlap syndrome, lichen sclerosus (lichen sclerosus et atrophicus), lichen striatus (Blaschko linear acquired inflammatory skin eruption), Lichenoid dermatitis, Lichenoid reaction of graft-versus-host disease, linear lichen planus, peno-gingival syndrome, ulcerative lichen planus, vulvovaginal gingival syndrome, and vulvovaginal lichen planus.
Erysipeloid and erysipelas are both inflammations of the skin due to certain types of bacteria. Osgood-Schlatter disease is a common form of inflammation of the knee in active adolescents. It has no pharmaceutical treatment per se. Other inflammations of the knee include Sinding-Larsen-Johansson disease, Patellofemoral syndrome, and osteochondritis dissecans.
Pigmented villonodular synovitis (PVNS) is a joint disease characterized by inflammation and overgrowth of the joint lining, typically in the hip, knee, hands or ankle. It is considered to be a neoplastic growth, locally agressive, and comes in two forms, diffuse and nodular.
Adhesive capsulitis is a type of inflammation of the shoulder. Its origin is usually unknown.
There can be a generalized inflammatory response of the entire body. When it arises from a proven source of infection, it is called sepsis. When it does not, it is called systemic inflammatory response syndrome (SIRS). Both of these are characterized by extensive cytokine dysregulation.
The above list is by no means complete, but demonstrates the extraordinary breadth of causes, mechanisms and treatment (or lack thereof) for inflammation.
It should be noted that determining that a disorder is an inflammatory one is sometimes not an easy task. For example, it has taken decades of research to discover that the destruction of the central area of the retina, which is the hallmark of age-related macular degeneration, actually arises out of an inflammatory process, involving the Complement Pathway. This only became well established in 2005. It is entirely possible that a majority of disorders presented considered idiopathic --- including many untreatable disorders --- are in fact inflammatory disorders. An ongoing example of this difficulty is the question of insulin resistance, the underlying disorder in Type II Diabetes Mellitus and Metabolic Syndrome, and possibly a few other disorders as well. The inflammation hypothesis says that the enlarged fat cells drawn in macrophages, which excrete pro-inflammatory cytokines IL-6, α-TNF, and IL1-, which via their receptors activate JNK to block IRS-1. There is significant evidence for this, but no standard anti-inflammatory agents are effective against insulin resistance. The competing lipid overload hypothesis says that the enlarged fat cells leak fatty acids, causing DAGS to accumulate in muscle cells, which inhibit insulin signaling through PKCs and block IRS-1. At this time, there is no agreement on whether insulin resistance should be best understood as an inflammatory disorder. Thus, the art of record establishes a nexus between CIRP levels and cellular response to environmental stress and also discloses a role of CIRP in embryonic development. The art does not provide any guidance as to which disease(s) or conditions are characterized by elevated levels of CIRP and therefore an artisan has to establish the relationship between all inflammatory diseases and CIRP before antagonists/inhibitors could be used for treating a disease. Therefore, an artisan would have to carry out extensive experimentation to determine the relationship to biological activity of CIRP its relationship to a disease; such experimentation would be undue since the neither the art of record nor the specification provides sufficient guidance.
With respect to administration of a wide variety of structurally and functionally disparate agents: Successful utilization of many of the disclosed agents is unpredictable. Pharmaceutical therapies are unpredictable for the following reasons: 1. the peptide(s) or protein may be inactivated before producing an effect, i.e. such as proteolytic degradation, immunological inactivation or due to inherently short half-life of the peptide or protein; 2. the peptide(s) may not reach the target area, i.e. the peptide(s) or protein may not be able to cross the mucosa or may be adsorbed by fluids, cells and tissues where the peptide(s) or protein has no effect (3) other functional properties, known or unknown, may make the protein unsuitable for in vivo therapeutic use, i.e. such as adverse side effects prohibitive to the use of such treatment. See page 1338, footnote 7 of Ex parte Aggarwal, 23 USPQ2d 1334 (PTO BD. APP & Inter., 1992).
Thus, the instant specification does not provide sufficient teachings or objective evidence to guide the skilled artisan to practice the method as encompassed by the breadth of the instant claims. Rather, the instant claims encompass an invention of tremendous scope, and essentially call for trial and error by the skilled artisan to begin discovering the claimed invention without assisting the skilled artisan in such an endeavor, which is insufficient to constitute adequate enablement.
The scope of the claims must bear a reasonable correlation with the scope of enablement. In re Fisher, 166 USPQ 18(CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute.
In the instant case, the nature of the invention is complex, involving the administration of the compound of the formula (I) for treating or preventing immune-related disease or an inflammatory disease. It is noted that the courts have long settled that such is considered complex. See Ex parte Hitzeman, 9 USPQ2d 1821 (BPAI 1987), wherein it was determined that a single embodiment may provide broad enablement in cases involving predictable factors such as mechanical or electrical elements, but more will be required in cases that involve unpredictable factors such as most chemical reactions and physiological activity. See also In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970); Amqen Inc. v. Chuqai Pharmaceutical Co. Ltd.,927 F.2d 1200, 1212, 18 USPQ2d 1016, 1026 (Fed. Cir.), cert. denied, 502 U.S. 856 (1991).
Therefore, undue experimentation would be required to practice the claimed invention commensurate with the scope of the claims from the written disclosure alone. Reasonable correlation must exist between the scope of the claims and scope of enablement set forth. In view of the quantity of experimentation necessary, the limited working examples, the unpredictability of the art, the lack of sufficient guidance in the specification, and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
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 4 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The claim recites a method of preparing a compound, but fails to provide any steps or actions that define the method. The claim, as written, is indefinite because it does not particularly point out and distinctly claim what steps are involved. To meet the definitiveness requirement, the claim must clearly recite the actions taken to achieve the preparation.
Conclusion
Claims 1-20 are not allowed.
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/JEAN P CORNET/ Primary Examiner, Art Unit 1628