An invention is not a thing, 4

An invention is not a thing, it is a collection or set.

Consider this invention, “Compounds.” A US patent (10,428,078) was issued to GlaxoSmithKline Intellectual Property Development Limited on October 1, 2019–just a few days ago. An earlier patent (10,125,141) with some other claims issued in 2018. There are published applications or issued patents related to these US patents derived from a common PCT patent application in a number of other countries as well, including Argentina, Australia, Brazil, Canada, China, Spain, Japan, Korea, Russia, Taiwan, and Uruguay.

Here is the Abstract:

The present invention relates to novel compounds that inhibit Lp-PLA.sub.2 activity, processes for their preparation, to compositions containing them and to their use in the treatment of diseases associated with the activity of Lp-PLA.sub.2, for example Alzheimer’s disease.

So the invention relates to novel compounds that affect the activity of an enzyme that changes fats into fatty acids that are implicated in various diseases, such as Alzheimer’s disease. If an invention were a thing, we might expect to find here a claim for one compound that provides a therapeutic benefit in the treatment of Alzheimer’s. But that’s not the case. It’s not one compound, it’s not one disease.

Here is the Field of the Invention:

The present invention relates to novel tricyclic imidazo-pyrimidinone compounds, processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them, and their use in therapy for the treatment of diseases mediated by Lp-PLA.sub.2.

Any disease “mediated” by a basic enzyme is within the scope of the invention–and potentially within the scope of the patent’s claims.

Lp-PLA.sub.2 is “lipoprotein-associated phospholipase A2.” Here’s a brief description at Science Direct:

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a monomeric enzyme that catalyzes oxidized phospholipid found in LDL into lysophosphatidylcholine and oxidized fatty acid, both of which are atherogenic.

Lp-PLA2 “is an emerging biomarker for vascular disease.” If you have more of this stuff in your bloodstream, so the theory goes, you are at greater risk for heart and vascular problems.

Our patent, however, is much broader. It lists a range of diseases that may involve Lp-PLA2 activity:

Examples of diseases include atherosclerosis (e.g. peripheral vascular atherosclerosis and cerebrovascular atherosclerosis), diabetes, hypertension, angina pectoris, after ischaemia and reperfusion, rheumatoid arthritis, stroke, inflammatory conditions of the brain such as Alzheimer’s Disease, various neuropsychiatric disease such as schizophrenia, myocardial infarction, ischaemia, reperfusion injury, sepsis, acute and chronic inflammation, and psoriasis.

The patent’s “Background” discussion  adds others: dementia, multiple sclerosis, ALS, Parkinson’s, diabetic ocular disease, glaucoma, and age-related macular degeneration.

In view of the number of pathological responses that are mediated by Lp-PLA.sub.2, attempts have been made to prepare compounds that inhibit its activity. Though a number of such compounds have been disclosed in the art, there remains a continuing need for inhibitors of Lp-PLA.sub.2 which can be used in the treatment of a variety of conditions.

So–a new set of compounds that appear to inhibit the activity of an enzyme implicated in a wide range of diseases involving inflammation.

Here’s the first claim of the patent (of 28). I don’t expect you to actually read it. Just look at it.

1. A compound of Formula (I-3) or a pharmaceutically acceptable salt thereof: ##STR00743## wherein R.sup.1 is selected from the group consisting of H, C.sub.1-3alkyl and –C(O)–C.sub.1-3alkyl; and R.sup.2 and R.sup.3 together with the carbon to which they are attached form a 4, 5 or 6 membered saturated ring, which ring optionally contains one heteroatom ring member selected from N or O, and is optionally substituted with one substituent of -L-K, wherein L is selected from the group consisting of C(O), CH.sub.2, and S(O).sub.2, and K is selected from the group consisting of C.sub.1-3alkyl, phenyl, and C.sub.3-6cycloalkyl; or R.sup.1 and R.sup.2 together with the nitrogen and carbon to which they are attached form a 5-membered saturated heterocyclic ring, which ring optionally contains one or two additional heteroatom ring member independently selected from the group consisting of N, O, C(O), S, S(O), and S(O).sub.2, and is optionally substituted with one or more substituents independently selected from the group consisting of OH, halo, NR.sup.1aR.sup.1b, COOH, and –Y–R.sup.c, wherein Y is absent or is selected from the group consisting of C(O), S(O).sub.2, –C(O)–C(O)–, and CH.sub.2, and R.sup.c is selected from the group consisting of C.sub.1-5alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR.sup.2aR.sup.2b, C.sub.3-6 cycloalkyl, and –COOH, C.sub.1-3haloalkyl, C.sub.1-3alkoxyl, NR.sup.3aR.sup.3b, –(CH.sub.2).sub.p–C(O)–O–C.sub.1-3alkyl, wherein p is 1, 2, or 3 and the –(CH.sub.2).sub.p– is optionally substituted by one or more methyl, –(CH.sub.2).sub.q–C.sub.3-6 cycloalkyl wherein q is 1, 2, or 3, the cycloalkyl is optionally substituted with NR.sup.4aR.sup.4b, and the –(CH.sub.2).sub.q– is optionally substituted by one or more methyl, and heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halo and NR.sup.5aR.sup.5b, wherein R.sup.1a, R.sup.1b, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, R.sup.5a, and R.sup.5b are independently H or C.sub.1-3alkyl; and R.sup.3 is H; each occurrence of R.sup.4 is independently H or D; X is absent or is selected from the group consisting of –O–, –NH–, and –N (C.sub.1-3 alkyl)-, n is 1 or 2; or X is –O–CH.sub.2– bicyclo[1.1.1]pentanyl-CH.sub.2–O– and n is 0; A is ##STR00744## wherein R.sup.5 and R.sup.9 are independently H or halo, Z’ is N or CR.sup.6, Z is N or CR.sup.8, wherein R.sup.6 and R.sup.8 are independently selected from the group consisting of H, CN, halo, C.sub.1-3alkyl, C.sub.1-3haloalkyl, –S(O).sub.2–C.sub.1-3alkyl and –S(O)–C.sub.1-3alkyl, and V is CR.sup.7, wherein R.sup.7 is -Q-(CH.sub.2).sub.m–W, wherein Q is O, N, or CH.sub.2, m is 0 or 1, and W is 6 membered heteroaryl, wherein the 6 membered heteroaryl is selected from the group consisting of pyridazinyl, pyrimidinyl, pyrazinyl, and triaziny, and wherein said heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of C.sub.1-3haloalkyl, CN, halo and C.sub.1-5alkyl.

This claim uses “optionally” ten times for variations on the chemical composition of the the class of compounds that has been invented. The detailed description of the invention provides descriptions of the compounds such as (gaze at this):

In a first aspect, this invention relates to compounds of Formula (I) and salts (e.g., pharmaceutically acceptable salts) thereof,

##STR00003## wherein R.sup.1 is selected from the group consisting of H, C.sub.1-3alkyl and –C(O)–C.sub.1-3alkyl; and R.sup.2 and R.sup.3 together with the carbon to which they are attached form a 4, 5 or 6 membered saturated ring, which ring optionally contains one heteroatom ring member selected from N or O, and is optionally substituted with one substituent of -L-K, wherein L is selected from the group consisting of C(O), CH.sub.2, and S(O).sub.2, and K is selected from the group consisting of C.sub.1-3alkyl, phenyl, and C.sub.3-6cycloalkyl; or R.sup.1 and R.sup.2 together with the nitrogen and carbon to which they are attached form a 5 or 6-membered heterocyclic saturated ring, which ring optionally contains one or two additional heteroatom ring member independently selected from the group consisting of N, O, C(O), S, S(O), and S(O).sub.2, and is optionally substituted with one or more (e.g., one, or one or two) substituents independently selected from the group consisting of OH, halo, NR.sup.1aR.sup.1b, COOH, and –Y–R.sup.c, wherein Y is absent or is selected from the group consisting of C(O), S(O).sub.2, –C(O)–C(O)–, and CH.sub.2, and R.sup.c is selected from the group consisting of C.sub.1-5alkyl optionally substituted with one or more (e.g., one, one or two, or one, two or three) substituents independently selected from the group consisting of NR.sup.2aR.sup.2b, C.sub.3-6 cycloalkyl, and –COOH, C.sub.1-3haloalkyl, C.sub.1-3alkoxyl, NR.sup.3aR.sup.3b, –(CH.sub.2).sub.p–C(O)–O–C.sub.1-3alkyl, wherein p is 1, 2, or 3 and the –(CH.sub.2).sub.p– is optionally substituted by one or more (e.g., one or one or two) methyl, –(CH.sub.2).sub.q–C.sub.3-6 cycloalkyl, wherein q is 1, 2, or 3, wherein the cycloalkyl is optionally substituted with NR.sup.4aR.sup.4b, and the –(CH.sub.2).sub.q– is optionally substituted by one or more (e.g., one or one or two) methyl, and heterocyclyl optionally substituted with one or more (e.g., one or one or two) substituents independently selected from the group consisting of halo and NR.sup.5aR.sup.5b, wherein R.sup.1a, R.sup.1b, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, R.sup.5a, and R.sup.5b are independently H or C.sub.1-3alkyl; and R.sup.3 is H; each occurrence of R.sup.4 is independently H or D; X is absent or is selected from the group consisting of –O–, –NH–, and –N–(C.sub.1-3 alkyl)-, n is 1 or 2; or X is –O–CH.sub.2– bicyclo[1.1.1]pentanyl-CH.sub.2–O– and n is 0; and A is unsubstituted thiophenyl, or A is

##STR00004## wherein R.sup.5 and R.sup.9 are independently H or halo, Z’ is N or CR.sup.6, Z is N or CR.sup.8, wherein R.sup.6 and R.sup.8 are independently selected from the group consisting of H, CN, halo, C.sub.1-3alkyl, C.sub.1-3haloalkyl, –S(O).sub.2–C.sub.1-3alkyl and –S(O)–C.sub.1-3alkyl, and V is N or CR.sup.7, wherein R.sup.7 is selected from the group consisting of H, halo, CN, C.sub.1-3alkyl, C.sub.1-3haloalkyl, and –S(O).sub.2–C.sub.1-3alkyl, or R.sup.7 is -Q-(CH.sub.2).sub.m–W, wherein Q is O, N, or CH.sub.2, m is 0 or 1, and W is selected from the group consisting of C.sub.3-6 cycloalkyl, heterocyclyl, 5 or 6 membered heteroaryl and phenyl, wherein said cycloalkyl, heterocyclyl, heteroaryl or phenyl is optionally substituted with one or more (e.g., one, or one or two) substituents independently selected from the group consisting of C.sub.1-3haloalkyl, CN, halo and C.sub.1-5 alkyl; or when Z or Z’ is CR.sup.6 and V is CR.sup.7, R.sup.6 and R.sup.7 together may form a 4,7-dioxaspiro[2.6]nonane; with the proviso that the compound of Formula (I) is not 2-fluoro-5-(((9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidaz- o[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile, 7-(2,3-difluorophenethyl)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imi- dazo[1,2-c]pyrimidin-9(2H)-one, 7-((2,3-difluorobenzyl)amino)-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidaz- o[1,2-c]pyrimidine-3,9(2H,4H)-dione, 7-((3,4-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imi- dazo[5,1-c][1,4]thiazin-9(1H)-one 2,2-dioxide, 7-((2,3-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imi- dazo[5,1-c][1,4]thiazin-9(1H)-one-2-oxide, or 7-((2,3-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imi- dazo[5,1-c][1,4]thiazin-9(1H)-one-2,2-dioxide.

The discussion of compounds goes on in this manner through additional claims. Claims 1 to 21 along with 25 all involve variations on the structures of the compounds claimed. You get the idea. There are many of them. Any one of which might be used to inhibit the target enzyme’s activity, and any change in that activity then might be considered therapeutic.

The patent also introduces a definition of disease:

As used herein, unless otherwise indicated, “disease” refers to any alteration in state of the body or of some of the organs, interrupting or disturbing the performance of the functions and/or causing symptoms such as discomfort, dysfunction, distress, or even death to the person afflicted or those in contact with a person. A disease can also include a distemper, ailing, ailment, malady, disorder, sickness, illness, complaint, interdisposition and/or affectation.

Basically anything out of the ordinary, from discomfort to death. And more, the patent defines lists of diseases:

As used herein, unless otherwise indicated, “neurodegeneration disease” as used herein refers to a varied assortment of central nervous system disorder characterized by gradual and progressive loss of neural tissue and/or neural tissue function. A neurodegeneration disease is a class of neurological disease where the neurological disease is characterized by a gradual and progressive loss of neural tissue, and/or altered neurological function, typically reduced neurological function as a result of a gradual and progressive loss of neural tissue. In certain embodiments, the neurodegeneration diseases described herein include neurodegeneration diseases where there is a defective blood brain barrier, for example a permeable blood brain barrier. Examples of neurodegeneration diseases where there is a defective blood brain barrier include, but are not limited to, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, vascular dementia and the like.

As used herein, unless otherwise indicated, “vascular dementia” is also referred to as “multi-infarct dementia”, which refers to a group of syndromes caused by different mechanisms, which all result in vascular lesions in the brain. The main subtypes of vascular dementia are, for example, vascular mild cognitive impairment, multi-infarct dementia, vascular dementia due to a strategic single infarct, (affecting the thalamus, the anterior cerebral artery, the parietal lobes or the cingulated gyrus), vascular dementia due to hemorrhagic lesions, small vessel disease (including, e.g. vascular dementia due to lacunar lesions and Binswanger disease), and mixed dementia.

As used herein, unless otherwise indicated, “metabolic bone disease” as used herein refers to a varied assortment of bone diseases characterized by gradual and progressive loss of bone tissue. Metabolic bone diseases described herein are metabolic bone diseases where there is a condition of diffusely decreased bone density and/or diminished bone strength. Such diseases are characterized by histological appearance. Exemplary metabolic bone diseases include, but are not limited to, osteoporosis which is characterized by decreased mineral and bone matrix, and osteomalacia which is characterized by decreased mineral but intact bone matrix.

As used herein, unless otherwise indicated, “osteopenic diseases” or “osteopenia” are used interchangeably herein, and refer to conditions with decreased calcification and/or bone density, and is a descriptive term used to refer to all skeletal systems in which decreased calcification and/or bone density is observed. Osteopenia also refers to a reduced bone mass due to inadequate osteiod synthesis.

As used herein, unless otherwise indicated, “osteoporosis” refers to conditions in which mineral and/or bone matrix are decreased and/or bone mass is reduced.

Again, get a sense of the range of things implicated in the use of a class of compounds that affects the activity of an enzyme that is implicated in inflammation and therefore may be therapeutic for any “disease” within the patent’s definition.

Claims 22 to 28 then claim various classes of disease–neurodegeneration disease (22), Alzheimer’s (23), and atherosclerosis (24).

Here’s claim 22:

A method for treating neurodegeneration disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to claim 1.

Look at “in a subject.” In an earlier US patent (10,125,141), on the same subject matter, GlaxoSmithKline includes a claim 27

27. A method for treating neurodegeneration disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to claim 11.

And then makes clear that “subject” could be any living thing in need of therapy:

30. The method according to claim 27, wherein the subject is a human.

Left out of the claims in our patent, but taught, are the bone diseases. Some claims were canceled in the patent application–perhaps those were the ones. It may be that another patent application in the works will deal with bone diseases.

As it is, the claims directed to the class of compounds means that no one can make, use, or sell these compounds for any purpose, not just for therapeutic purposes.

The invention then is the class of compounds, methods of making the compounds, the formulation of the compounds into therapeutic agents, the application of those therapeutic agents to affect the activity of a specified enzyme, the treatment of any disease that may involve the specified enzyme, and methods of any such treatment–and also for preventing such diseases.

If I were to take a guess, I would say that this expansive set of claims began in China-based a research effort to identify a new compound targeting activity of an important enzyme implicated in a wide range of diseases but especially Alzheimer’s. One of the Chinese co-inventors (if I have correctly identified him) specializes in neurology and Parkinson’s disease. The two other Chinese co-inventors are (now former) long-time GSK scientists, now with Chinese pharmaceutical companies.

GSK then–so it appears–involved its scientists in the US and UK to expand the possible forms of the compound and the possible uses. Then GSK filed a patent application in China as a PCT application in 2014, claiming a broad class of compounds, methods, treatments, and diseases. The company has now moved to national phase filings. Here is  information from Espacenet, the European patent search service.

A compound, a potential treatment, a target disease. That’s invention as a thing. It’s easy to imagine an invention as a thing. Perhaps the discovery of these compounds started that way. There’s often an “entry gate”–a discovery or realization can be a kind of door into an area to explore. The GSK patents claim not only that door–a compound, a potential treatment, a target disease–but also everything to be explored past that gate. All the compounds that can be related as variants. The initial compound becomes an instance of a category of compounds. The target disease becomes an instance of all such diseases that might have anything to do with the target enzyme. Add methods of making the compounds, methods of preparing treatments, methods of treating. It’s great patent work.

The patents in all these countries mean that, effectively, no one may conduct research using these compounds but for GSK’s approval–in each of these countries where one (or more) patents has issued, GSK has a government-granted right to exclude all others from making and using these compounds, including even for use in research. And why do research on these compounds anyway, if all roads must for the next 15 years or so, move through GSK? Only perhaps if one hoped that GSK would purchase the new work. Otherwise, in effect, one is donating research effort to the company. While the company might welcome such generosity, we might wonder if that’s an appropriate use for publicly funded research–whether through a government or a nonprofit foundation. For that matter, is it appropriate for a government or nonprofit to fund research on GSK’s compounds with the hope of selling something exclusively to GSK? Would making money on the transaction really be an acceptable outcome? A “success”?

While someone might think up a new use for these compounds, not anticipated by GSK’s patents or the published literature–such as targeting a different enzyme or use in a non-medical setting–and could then obtain, perhaps, a patent of their own, they would still have to go through GSK to obtain a license to make and use any compound within the scope of GSK’s claims. Their patents do not cover just a compound and its medical use with, say, Alzheimer’s disease. Rather, their patents foreclose an entire area of the compounds use at all, and an entire area of the compounds’ use in medicine, for the duration of the patents–or until, say, about 2034.

This is typical stuff. Next, we look at how this typical stuff–that invention is not a thing–plays in US federal research invention policy, which treats invention as if it were a thing.

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